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PMC0
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10.1038%2Fcelldisc.2016.47
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introduction
n6:contains
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Bloom syndrome (BS) and Fanconi anemia (FA) are two rare genetic diseases sharing several features, such as genomic instability, cancer predisposition and developmental abnormalities [1–>>3<<]. In addition, each disease has its own characteristics. For example, the cells from BS patients display a higher frequency of sister-chromatid exchanges (SCEs), which can lead to the loss of heterozygosity and increased cancer risks.
n3:mentions
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BS is caused by mutations in BLM gene, which belongs to the RecQ DNA helicase family conserved from Escherichia coli to humans [>>4<<]. In addition to BLM, two other human RecQ helicases are also mutated in the genomic instability diseases, Werner Syndrome [5] and Rothmund–Thomson syndrome, respectively [6], highlighting the essentiality of these enzymes in protecting
n3:mentions
n2:7585968
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_:vb59047204
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In addition to BLM, two other human RecQ helicases are also mutated in the genomic instability diseases, Werner Syndrome [>>5<<] and Rothmund–Thomson syndrome, respectively [6], highlighting the essentiality of these enzymes in protecting genome integrity.
n3:mentions
n2:8602509
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In addition to BLM, two other human RecQ helicases are also mutated in the genomic instability diseases, Werner Syndrome [5] and Rothmund–Thomson syndrome, respectively [>>6<<], highlighting the essentiality of these enzymes in protecting genome integrity.
n3:mentions
n2:10319867
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_:vb59047206
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BLM has been purified as a part of the DNA double Holliday junction dissolvasome complex that contains BLM, topoisomerase 3a (Top3a), RMI1 and RMI2 [7–>>10<<]. The four components of this complex work coordinately to catalyze dissolution of double Holliday junctions, which are intermediates produced during the repair of DNA double-strand breaks. This leads to suppression of crossover
n3:mentions
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_:vb59047207
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This leads to suppression of crossover recombination and SCEs [>>11<<]. BLM is also recruited to stalled replication forks and is required for efficient recovery of the stalled forks [12–15].
n3:mentions
n2:14685245
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_:vb59047208
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BLM is also recruited to stalled replication forks and is required for efficient recovery of the stalled forks [12–>>15<<].
n3:mentions
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_:vb59047209
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Unlike BS that is caused by mutations in a single gene, at least 20 genes (FANC-A, B, C, D1, D2, E, F, G, I, J, L, M, N, O, P, Q, R, S, T and U) have been identified in which mutations can cause FA [>>1<<, 2, 16, 17]. The FANC gene products have been shown to act at various steps in the FA DNA damage response pathway to repair ICLs.
n3:mentions
n2:17768402
Subject Item
_:vb59047210
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n3:Context
rdf:value
Unlike BS that is caused by mutations in a single gene, at least 20 genes (FANC-A, B, C, D1, D2, E, F, G, I, J, L, M, N, O, P, Q, R, S, T and U) have been identified in which mutations can cause FA [1, >>2<<, 16, 17]. The FANC gene products have been shown to act at various steps in the FA DNA damage response pathway to repair ICLs.
n3:mentions
n2:26512453
Subject Item
_:vb59047211
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Unlike BS that is caused by mutations in a single gene, at least 20 genes (FANC-A, B, C, D1, D2, E, F, G, I, J, L, M, N, O, P, Q, R, S, T and U) have been identified in which mutations can cause FA [1, 2, >>16<<, 17]. The FANC gene products have been shown to act at various steps in the FA DNA damage response pathway to repair ICLs.
n3:mentions
n2:23325218
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_:vb59047212
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Unlike BS that is caused by mutations in a single gene, at least 20 genes (FANC-A, B, C, D1, D2, E, F, G, I, J, L, M, N, O, P, Q, R, S, T and U) have been identified in which mutations can cause FA [1, 2, 16, >>17<<]. The FANC gene products have been shown to act at various steps in the FA DNA damage response pathway to repair ICLs.
n3:mentions
n2:27208205
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_:vb59047213
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Acting upstream of this pathway is the FA core complex that contains eight FA proteins (FANC-A, B, C, E, F, G, L and M) and five FA-associated proteins (FAAP100, FAAP24, FAAP20, MHF1 and MHF2) [18–>>28<<]. The main function of this complex is to monoubiquitinate the FA FANCI–FANCD2 complex (abbreviated as ID complex) in response to DNA damage and replication stress [29]. The ubiquitinated FA ID complex then recruits downstream FA
n3:mentions
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The main function of this complex is to monoubiquitinate the FA FANCI–FANCD2 complex (abbreviated as ID complex) in response to DNA damage and replication stress [>>29<<]. The ubiquitinated FA ID complex then recruits downstream FA proteins, as well as other repair molecules, to remove ICLs and restore stalled replication forks. FANCM and its dsDNA binding partner, MHF1 and MHF2, also constitute an
n3:mentions
n2:22751496
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_:vb59047215
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FANCM and its dsDNA binding partner, MHF1 and MHF2, also constitute an independent complex, FANCM–MHF, which is conserved from yeast to human [>>23<<, 24]. This complex acts in a replication traverse pathway that enables the replication machinery to restart past the ICLs and complete the essential process of DNA synthesis at the expense of leaving the ICLs unrepaired [30]. These
n3:mentions
n2:20347428
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FANCM and its dsDNA binding partner, MHF1 and MHF2, also constitute an independent complex, FANCM–MHF, which is conserved from yeast to human [23, >>24<<]. This complex acts in a replication traverse pathway that enables the replication machinery to restart past the ICLs and complete the essential process of DNA synthesis at the expense of leaving the ICLs unrepaired [30]. These residual
n3:mentions
n2:20347429
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This complex acts in a replication traverse pathway that enables the replication machinery to restart past the ICLs and complete the essential process of DNA synthesis at the expense of leaving the ICLs unrepaired [>>30<<]. These residual ICLs will be subsequently removed by post-replication repair mechanisms.
n3:mentions
n2:24207054
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FANCM is a key component of both the FA core and FANCM–MHF complexes, and possesses critical DNA processing activities and functions [>>19<<, 23, 24, 31–35].
n3:mentions
n2:16116422
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FANCM is a key component of both the FA core and FANCM–MHF complexes, and possesses critical DNA processing activities and functions [19, >>23<<, 24, 31–35].
n3:mentions
n2:20347428
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FANCM is a key component of both the FA core and FANCM–MHF complexes, and possesses critical DNA processing activities and functions [19, 23, >>24<<, 31–35]. First, FANCM has specific binding activity for branched DNA structures, such as forks and Holliday Junctions; and this binding activity is required for recruiting FA core complex to damaged DNA and for monoubiquitination of the
n3:mentions
n2:20347429
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FANCM is a key component of both the FA core and FANCM–MHF complexes, and possesses critical DNA processing activities and functions [19, 23, 24, 31–>>35<<]. First, FANCM has specific binding activity for branched DNA structures, such as forks and Holliday Junctions; and this binding activity is required for recruiting FA core complex to damaged DNA and for monoubiquitination of the FA ID
n3:mentions
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FANCM has specific binding activity for branched DNA structures, such as forks and Holliday Junctions; and this binding activity is required for recruiting FA core complex to damaged DNA and for monoubiquitination of the FA ID complex [>>23<<, 32, 33, 36, 37]. Second, FANCM harbors an ATP-dependent translocase activity that can remodel forks and Holliday junctions [19, 32, 33].
n3:mentions
n2:20347428
Subject Item
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has specific binding activity for branched DNA structures, such as forks and Holliday Junctions; and this binding activity is required for recruiting FA core complex to damaged DNA and for monoubiquitination of the FA ID complex [23, >>32<<, 33, 36, 37]. Second, FANCM harbors an ATP-dependent translocase activity that can remodel forks and Holliday junctions [19, 32, 33].
n3:mentions
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specific binding activity for branched DNA structures, such as forks and Holliday Junctions; and this binding activity is required for recruiting FA core complex to damaged DNA and for monoubiquitination of the FA ID complex [23, 32, >>33<<, 36, 37]. Second, FANCM harbors an ATP-dependent translocase activity that can remodel forks and Holliday junctions [19, 32, 33].
n3:mentions
n2:18285517
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binding activity for branched DNA structures, such as forks and Holliday Junctions; and this binding activity is required for recruiting FA core complex to damaged DNA and for monoubiquitination of the FA ID complex [23, 32, 33, >>36<<, 37]. Second, FANCM harbors an ATP-dependent translocase activity that can remodel forks and Holliday junctions [19, 32, 33].
n3:mentions
n2:19465393
Subject Item
_:vb59047226
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binding activity for branched DNA structures, such as forks and Holliday Junctions; and this binding activity is required for recruiting FA core complex to damaged DNA and for monoubiquitination of the FA ID complex [23, 32, 33, 36, >>37<<]. Second, FANCM harbors an ATP-dependent translocase activity that can remodel forks and Holliday junctions [19, 32, 33].
n3:mentions
n2:19423727
Subject Item
_:vb59047227
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Second, FANCM harbors an ATP-dependent translocase activity that can remodel forks and Holliday junctions [>>19<<, 32, 33]. This activity is required for recovery of stalled replication forks [38–40], for activation of ATR kinase in response to replication stress [34, 40, 41], for cellular resistance to ICLs [33, 36, 37] and for replication traverse
n3:mentions
n2:16116422
Subject Item
_:vb59047228
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Second, FANCM harbors an ATP-dependent translocase activity that can remodel forks and Holliday junctions [19, >>32<<, 33]. This activity is required for recovery of stalled replication forks [38–40], for activation of ATR kinase in response to replication stress [34, 40, 41], for cellular resistance to ICLs [33, 36, 37] and for replication traverse of
n3:mentions
n2:18206976
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_:vb59047229
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Second, FANCM harbors an ATP-dependent translocase activity that can remodel forks and Holliday junctions [19, 32, >>33<<]. This activity is required for recovery of stalled replication forks [38–40], for activation of ATR kinase in response to replication stress [34, 40, 41], for cellular resistance to ICLs [33, 36, 37] and for replication traverse of ICLs
n3:mentions
n2:18285517
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_:vb59047230
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This activity is required for recovery of stalled replication forks [38–>>40<<], for activation of ATR kinase in response to replication stress [34, 40, 41], for cellular resistance to ICLs [33, 36, 37] and for replication traverse of ICLs [30]; but is dispensable for monoubiquitination of FANCD2 [33, 36, 37].
n3:mentions
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_:vb59047231
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This activity is required for recovery of stalled replication forks [38–40], for activation of ATR kinase in response to replication stress [>>34<<, 40, 41], for cellular resistance to ICLs [33, 36, 37] and for replication traverse of ICLs [30]; but is dispensable for monoubiquitination of FANCD2 [33, 36, 37].
n3:mentions
n2:20670894
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_:vb59047232
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This activity is required for recovery of stalled replication forks [38–40], for activation of ATR kinase in response to replication stress [34, >>40<<, 41], for cellular resistance to ICLs [33, 36, 37] and for replication traverse of ICLs [30]; but is dispensable for monoubiquitination of FANCD2 [33, 36, 37].
n3:mentions
n2:20057355
Subject Item
_:vb59047233
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This activity is required for recovery of stalled replication forks [38–40], for activation of ATR kinase in response to replication stress [34, 40, >>41<<], for cellular resistance to ICLs [33, 36, 37] and for replication traverse of ICLs [30]; but is dispensable for monoubiquitination of FANCD2 [33, 36, 37].
n3:mentions
n2:20160754
Subject Item
_:vb59047234
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This activity is required for recovery of stalled replication forks [38–40], for activation of ATR kinase in response to replication stress [34, 40, 41], for cellular resistance to ICLs [>>33<<, 36, 37] and for replication traverse of ICLs [30]; but is dispensable for monoubiquitination of FANCD2 [33, 36, 37].
n3:mentions
n2:18285517
Subject Item
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This activity is required for recovery of stalled replication forks [38–40], for activation of ATR kinase in response to replication stress [34, 40, 41], for cellular resistance to ICLs [33, >>36<<, 37] and for replication traverse of ICLs [30]; but is dispensable for monoubiquitination of FANCD2 [33, 36, 37].
n3:mentions
n2:19465393
Subject Item
_:vb59047236
rdf:type
n3:Context
rdf:value
This activity is required for recovery of stalled replication forks [38–40], for activation of ATR kinase in response to replication stress [34, 40, 41], for cellular resistance to ICLs [33, 36, >>37<<] and for replication traverse of ICLs [30]; but is dispensable for monoubiquitination of FANCD2 [33, 36, 37].
n3:mentions
n2:19423727
Subject Item
_:vb59047237
rdf:type
n3:Context
rdf:value
This activity is required for recovery of stalled replication forks [38–40], for activation of ATR kinase in response to replication stress [34, 40, 41], for cellular resistance to ICLs [33, 36, 37] and for replication traverse of ICLs [>>30<<]; but is dispensable for monoubiquitination of FANCD2 [33, 36, 37].
n3:mentions
n2:24207054
Subject Item
_:vb59047238
rdf:type
n3:Context
rdf:value
forks [38–40], for activation of ATR kinase in response to replication stress [34, 40, 41], for cellular resistance to ICLs [33, 36, 37] and for replication traverse of ICLs [30]; but is dispensable for monoubiquitination of FANCD2 [>>33<<, 36, 37]. Third, FANCM contains multiple protein-interaction motifs and serves as a scaffold for assembly by MHF, FAAP24, the FA core complex, BS complex and PCNA [19, 22–24, 35, 42].
n3:mentions
n2:18285517
Subject Item
_:vb59047239
rdf:type
n3:Context
rdf:value
forks [38–40], for activation of ATR kinase in response to replication stress [34, 40, 41], for cellular resistance to ICLs [33, 36, 37] and for replication traverse of ICLs [30]; but is dispensable for monoubiquitination of FANCD2 [33, >>36<<, 37]. Third, FANCM contains multiple protein-interaction motifs and serves as a scaffold for assembly by MHF, FAAP24, the FA core complex, BS complex and PCNA [19, 22–24, 35, 42].
n3:mentions
n2:19465393
Subject Item
_:vb59047240
rdf:type
n3:Context
rdf:value
[38–40], for activation of ATR kinase in response to replication stress [34, 40, 41], for cellular resistance to ICLs [33, 36, 37] and for replication traverse of ICLs [30]; but is dispensable for monoubiquitination of FANCD2 [33, 36, >>37<<]. Third, FANCM contains multiple protein-interaction motifs and serves as a scaffold for assembly by MHF, FAAP24, the FA core complex, BS complex and PCNA [19, 22–24, 35, 42].
n3:mentions
n2:19423727
Subject Item
_:vb59047241
rdf:type
n3:Context
rdf:value
Third, FANCM contains multiple protein-interaction motifs and serves as a scaffold for assembly by MHF, FAAP24, the FA core complex, BS complex and PCNA [>>19<<, 22–24, 35, 42].
n3:mentions
n2:16116422
Subject Item
_:vb59047242
rdf:type
n3:Context
rdf:value
Third, FANCM contains multiple protein-interaction motifs and serves as a scaffold for assembly by MHF, FAAP24, the FA core complex, BS complex and PCNA [19, 22–>>24<<, 35, 42]. Mutations in FANCM that eliminate its interactions with its partners can disrupt the FA pathway, the replication traverse pathway, cellular resistance to ICLs, and/or suppression of SCEs [35, 42–44].
n3:mentions
n2:20347428 n2:20347429 n2:17289582
Subject Item
_:vb59047243
rdf:type
n3:Context
rdf:value
Third, FANCM contains multiple protein-interaction motifs and serves as a scaffold for assembly by MHF, FAAP24, the FA core complex, BS complex and PCNA [19, 22–24, >>35<<, 42]. Mutations in FANCM that eliminate its interactions with its partners can disrupt the FA pathway, the replication traverse pathway, cellular resistance to ICLs, and/or suppression of SCEs [35, 42–44].
n3:mentions
n2:20064461
Subject Item
_:vb59047244
rdf:type
n3:Context
rdf:value
Third, FANCM contains multiple protein-interaction motifs and serves as a scaffold for assembly by MHF, FAAP24, the FA core complex, BS complex and PCNA [19, 22–24, 35, >>42<<]. Mutations in FANCM that eliminate its interactions with its partners can disrupt the FA pathway, the replication traverse pathway, cellular resistance to ICLs, and/or suppression of SCEs [35, 42–44].
n3:mentions
n2:26825464
Subject Item
_:vb59047245
rdf:type
n3:Context
rdf:value
Mutations in FANCM that eliminate its interactions with its partners can disrupt the FA pathway, the replication traverse pathway, cellular resistance to ICLs, and/or suppression of SCEs [>>35<<, 42–44].
n3:mentions
n2:20064461
Subject Item
_:vb59047246
rdf:type
n3:Context
rdf:value
Mutations in FANCM that eliminate its interactions with its partners can disrupt the FA pathway, the replication traverse pathway, cellular resistance to ICLs, and/or suppression of SCEs [35, 42–>>44<<].
n3:mentions
n2:24699063 n2:26825464 n2:22392978
Subject Item
_:vb59047247
rdf:type
n3:Context
rdf:value
Structural analyses have shown that the interface between FANCM and the BLM complex consists of residues from MM2 motif of FANCM, as well as residues from RMI1 and RMI2 [>>43<<]. Mutations that disrupt this interface result in increased cellular sensitivity to ICLs, defective recruitment of BLM to stalled replication forks and a higher frequency of SCEs [35, 43].
n3:mentions
n2:22392978
Subject Item
_:vb59047248
rdf:type
n3:Context
rdf:value
Mutations that disrupt this interface result in increased cellular sensitivity to ICLs, defective recruitment of BLM to stalled replication forks and a higher frequency of SCEs [>>35<<, 43]. However, the mechanism by which FANCM and BLM complex work together remains incompletely understood. Here we used chicken DT40 cells as a model to demonstrate that the interaction between FANCM and BLM complex is required for
n3:mentions
n2:20064461
Subject Item
_:vb59047249
rdf:type
n3:Context
rdf:value
Mutations that disrupt this interface result in increased cellular sensitivity to ICLs, defective recruitment of BLM to stalled replication forks and a higher frequency of SCEs [35, >>43<<]. However, the mechanism by which FANCM and BLM complex work together remains incompletely understood. Here we used chicken DT40 cells as a model to demonstrate that the interaction between FANCM and BLM complex is required for
n3:mentions
n2:22392978
Subject Item
_:vb59047250
rdf:type
n6:Section
dc:title
materials and methods
n6:contains
_:vb59047264 _:vb59047260 _:vb59047261 _:vb59047262 _:vb59047263 _:vb59047256 _:vb59047257 _:vb59047258 _:vb59047259 _:vb59047252 _:vb59047253 _:vb59047254 _:vb59047255 _:vb59047251
Subject Item
_:vb59047251
rdf:type
n3:Context
rdf:value
The chicken DT40 cell lines, including wild-type, FANCM−/−, FANCM knock-in mutants carrying C-terminal deletion or D203A point mutation [>>36<<]; RMI2−/−, RMI2−/− complemented with RMI2 wild-type or carrying K121A mutation [10]; FANCD2−/− [66], FANCD2−/−complemented with GFP-chicken FANCD2 [67]; FANCL−/− [68], FANCI−/− [69] and MHF1−/− [23], have been previously described.
n3:mentions
n2:19465393
Subject Item
_:vb59047252
rdf:type
n3:Context
rdf:value
The chicken DT40 cell lines, including wild-type, FANCM−/−, FANCM knock-in mutants carrying C-terminal deletion or D203A point mutation [36]; RMI2−/−, RMI2−/− complemented with RMI2 wild-type or carrying K121A mutation [>>10<<]; FANCD2−/− [66], FANCD2−/−complemented with GFP-chicken FANCD2 [67]; FANCL−/− [68], FANCI−/− [69] and MHF1−/− [23], have been previously described.
n3:mentions
n2:18923082
Subject Item
_:vb59047253
rdf:type
n3:Context
rdf:value
The chicken DT40 cell lines, including wild-type, FANCM−/−, FANCM knock-in mutants carrying C-terminal deletion or D203A point mutation [36]; RMI2−/−, RMI2−/− complemented with RMI2 wild-type or carrying K121A mutation [10]; FANCD2−/− [>>66<<], FANCD2−/−complemented with GFP-chicken FANCD2 [67]; FANCL−/− [68], FANCI−/− [69] and MHF1−/− [23], have been previously described.
n3:mentions
n2:15601828
Subject Item
_:vb59047254
rdf:type
n3:Context
rdf:value
FANCM knock-in mutants carrying C-terminal deletion or D203A point mutation [36]; RMI2−/−, RMI2−/− complemented with RMI2 wild-type or carrying K121A mutation [10]; FANCD2−/− [66], FANCD2−/−complemented with GFP-chicken FANCD2 [>>67<<]; FANCL−/− [68], FANCI−/− [69] and MHF1−/− [23], have been previously described.
n3:mentions
n2:16687415
Subject Item
_:vb59047255
rdf:type
n3:Context
rdf:value
knock-in mutants carrying C-terminal deletion or D203A point mutation [36]; RMI2−/−, RMI2−/− complemented with RMI2 wild-type or carrying K121A mutation [10]; FANCD2−/− [66], FANCD2−/−complemented with GFP-chicken FANCD2 [67]; FANCL−/− [>>68<<], FANCI−/− [69] and MHF1−/− [23], have been previously described.
n3:mentions
n2:17352736
Subject Item
_:vb59047256
rdf:type
n3:Context
rdf:value
carrying C-terminal deletion or D203A point mutation [36]; RMI2−/−, RMI2−/− complemented with RMI2 wild-type or carrying K121A mutation [10]; FANCD2−/− [66], FANCD2−/−complemented with GFP-chicken FANCD2 [67]; FANCL−/− [68], FANCI−/− [>>69<<] and MHF1−/− [23], have been previously described.
n3:mentions
n2:18931676
Subject Item
_:vb59047257
rdf:type
n3:Context
rdf:value
deletion or D203A point mutation [36]; RMI2−/−, RMI2−/− complemented with RMI2 wild-type or carrying K121A mutation [10]; FANCD2−/− [66], FANCD2−/−complemented with GFP-chicken FANCD2 [67]; FANCL−/− [68], FANCI−/− [69] and MHF1−/− [>>23<<], have been previously described.
n3:mentions
n2:20347428
Subject Item
_:vb59047258
rdf:type
n3:Context
rdf:value
The BLM−/− cells were generated by integrating a BLM-targeting vector into DT40 cells as previously described [>>71<<]. GFP-chicken BLM-wt [63] and K466A mutant expression vectors were introduced into BLM−/− cells, and transfections and selection of the clones were done as published procedures [66].
n3:mentions
n2:10880455
Subject Item
_:vb59047259
rdf:type
n3:Context
rdf:value
GFP-chicken BLM-wt [>>63<<] and K466A mutant expression vectors were introduced into BLM−/− cells, and transfections and selection of the clones were done as published procedures [66].
n3:mentions
n2:15616572
Subject Item
_:vb59047260
rdf:type
n3:Context
rdf:value
GFP-chicken BLM-wt [63] and K466A mutant expression vectors were introduced into BLM−/− cells, and transfections and selection of the clones were done as published procedures [>>66<<].
n3:mentions
n2:15601828
Subject Item
_:vb59047261
rdf:type
n3:Context
rdf:value
An anti-chicken FANCM polyclonal rabbit antibody (amino acids 773–879) was generated and purified with the method as previous described [>>19<<]. An anti-chicken FANCD2 antibody was previously described [72].
n3:mentions
n2:16116422
Subject Item
_:vb59047262
rdf:type
n3:Context
rdf:value
An anti-chicken FANCD2 antibody was previously described [>>72<<]. An anti-Flag antibody (Sigma-Aldrich, St Louis, MO, USA), anti-GFP antibody (Sigma-Aldrich), anti-actin antibody (Bethyl Laboratory, Motgomery, TX, USA), anti-α-Tubulin antibody (Cell Signaling, Danvers, MA, USA), anti-Chk1 antibody
n3:mentions
n2:22828868
Subject Item
_:vb59047263
rdf:type
n3:Context
rdf:value
The fractionation of cells into chromatin and soluble fractions has been described [>>23<<]. Briefly, a low-salt buffer (10 mm Tris-HCl pH 7.5, 10 mm NaCl, 3 mm MgCl2, 1 mm EDTA, 0.5% NP40, and a complete protease inhibitor cocktail (Roche)) was added to the cell pellets and incubated 5 min on ice. The cells were then
n3:mentions
n2:20347428
Subject Item
_:vb59047264
rdf:type
n3:Context
rdf:value
The assay was done as previously reported [>>30<<]. Briefly, the cells were treated with 5 μm Dig-TMP for 1 h and exposed to ultraviolet A irradiation in a Rayonet (Brandford, CT, USA) chamber at 3 J cm−2.
n3:mentions
n2:24207054
Subject Item
_:vb59047265
rdf:type
n6:Section
dc:title
results
n6:contains
_:vb59047266 _:vb59047267 _:vb59047268 _:vb59047269 _:vb59047270 _:vb59047271 _:vb59047272 _:vb59047273 _:vb59047274 _:vb59047275 _:vb59047276 _:vb59047277 _:vb59047278 _:vb59047279 _:vb59047280 _:vb59047281 _:vb59047282 _:vb59047283 _:vb59047284 _:vb59047285 _:vb59047286 _:vb59047287 _:vb59047288 _:vb59047289 _:vb59047290 _:vb59047291 _:vb59047292 _:vb59047293 _:vb59047294 _:vb59047295 _:vb59047296 _:vb59047297 _:vb59047298 _:vb59047299 _:vb59047300 _:vb59047301 _:vb59047302 _:vb59047303 _:vb59047304 _:vb59047305 _:vb59047306 _:vb59047307 _:vb59047308 _:vb59047309 _:vb59047310 _:vb59047311 _:vb59047312 _:vb59047313 _:vb59047314 _:vb59047315 _:vb59047316 _:vb59047317 _:vb59047318 _:vb59047319 _:vb59047320 _:vb59047321
Subject Item
_:vb59047266
rdf:type
n3:Context
rdf:value
drugs or under replication stress, many DNA repair proteins, including BLM and FANCD2, are re-distributed to the DNA damage sites or stalled replication forks, where they can be detected as large bright foci in the nuclei [12–>>14<<, 45]. However, it has been difficult to detect foci of FANCM in human cells following the treatment with DNA-reactive compounds, although we have been able to visualize recruitment of FANCM to laser-directed psoralen ICLs, because of the
n3:mentions
n2:14729972 n2:12606585 n2:15539948
Subject Item
_:vb59047267
rdf:type
n3:Context
rdf:value
drugs or under replication stress, many DNA repair proteins, including BLM and FANCD2, are re-distributed to the DNA damage sites or stalled replication forks, where they can be detected as large bright foci in the nuclei [12–14, >>45<<]. However, it has been difficult to detect foci of FANCM in human cells following the treatment with DNA-reactive compounds, although we have been able to visualize recruitment of FANCM to laser-directed psoralen ICLs, because of the
n3:mentions
n2:11239454
Subject Item
_:vb59047268
rdf:type
n3:Context
rdf:value
human cells following the treatment with DNA-reactive compounds, although we have been able to visualize recruitment of FANCM to laser-directed psoralen ICLs, because of the highly localized concentration of ICLs in the laser stripes [>>23<<]. To detect FANCM foci under regular drug-treated conditions, we generated an antibody against chicken FANCM, and found that this antibody readily detected FANCM in the bright nuclear foci in chicken DT40 cells treated with the drugs that
n3:mentions
n2:20347428
Subject Item
_:vb59047269
rdf:type
n3:Context
rdf:value
FANCM is an ATP-dependent DNA translocase that can remodel branched DNA, and this activity is critical for ATR activation, replication traverse of ICLs and SCE suppression [>>30<<, 32, 33, 36, 40, 41].
n3:mentions
n2:24207054
Subject Item
_:vb59047270
rdf:type
n3:Context
rdf:value
FANCM is an ATP-dependent DNA translocase that can remodel branched DNA, and this activity is critical for ATR activation, replication traverse of ICLs and SCE suppression [30, >>32<<, 33, 36, 40, 41].
n3:mentions
n2:18206976
Subject Item
_:vb59047271
rdf:type
n3:Context
rdf:value
FANCM is an ATP-dependent DNA translocase that can remodel branched DNA, and this activity is critical for ATR activation, replication traverse of ICLs and SCE suppression [30, 32, >>33<<, 36, 40, 41].
n3:mentions
n2:18285517
Subject Item
_:vb59047272
rdf:type
n3:Context
rdf:value
FANCM is an ATP-dependent DNA translocase that can remodel branched DNA, and this activity is critical for ATR activation, replication traverse of ICLs and SCE suppression [30, 32, 33, >>36<<, 40, 41]. We therefore investigated if this activity is also needed for FANCM recruitment to stalled forks, by utilizing a DT40 cell line carrying a knock-in point mutation within the Walker B box of the FANCM helicase domain, FANCM-D203A
n3:mentions
n2:19465393
Subject Item
_:vb59047273
rdf:type
n3:Context
rdf:value
FANCM is an ATP-dependent DNA translocase that can remodel branched DNA, and this activity is critical for ATR activation, replication traverse of ICLs and SCE suppression [30, 32, 33, 36, >>40<<, 41]. We therefore investigated if this activity is also needed for FANCM recruitment to stalled forks, by utilizing a DT40 cell line carrying a knock-in point mutation within the Walker B box of the FANCM helicase domain, FANCM-D203A
n3:mentions
n2:20057355
Subject Item
_:vb59047274
rdf:type
n3:Context
rdf:value
FANCM is an ATP-dependent DNA translocase that can remodel branched DNA, and this activity is critical for ATR activation, replication traverse of ICLs and SCE suppression [30, 32, 33, 36, 40, >>41<<]. We therefore investigated if this activity is also needed for FANCM recruitment to stalled forks, by utilizing a DT40 cell line carrying a knock-in point mutation within the Walker B box of the FANCM helicase domain, FANCM-D203A (Figure
n3:mentions
n2:20160754
Subject Item
_:vb59047275
rdf:type
n3:Context
rdf:value
investigated if this activity is also needed for FANCM recruitment to stalled forks, by utilizing a DT40 cell line carrying a knock-in point mutation within the Walker B box of the FANCM helicase domain, FANCM-D203A (Figure 2a) [>>36<<]. We found that the percentage of cells containing FANCM foci was reduced in these cells (from about 50 to 8%; Figure 2b and c), suggesting that FANCM strongly depends on its translocase activity to be efficiently recruited to the sites
n3:mentions
n2:19465393
Subject Item
_:vb59047276
rdf:type
n3:Context
rdf:value
Next, we investigated whether FANCM recruitment depends on its two DNA-binding partners, FAAP24 and MHF (Figure 2a), both of which have been shown to stimulate in vitro and in vivo function of FANCM [>>22<<, 23]. For FAAP24, we utilized a FANCM−/− DT40 cell line expressing a FANCM mutant lacking the C-terminal ERCC4-like nuclease domain FANCM-ΔC [36] (Figure 2a).
n3:mentions
n2:17289582
Subject Item
_:vb59047277
rdf:type
n3:Context
rdf:value
Next, we investigated whether FANCM recruitment depends on its two DNA-binding partners, FAAP24 and MHF (Figure 2a), both of which have been shown to stimulate in vitro and in vivo function of FANCM [22, >>23<<]. For FAAP24, we utilized a FANCM−/− DT40 cell line expressing a FANCM mutant lacking the C-terminal ERCC4-like nuclease domain FANCM-ΔC [36] (Figure 2a).
n3:mentions
n2:20347428
Subject Item
_:vb59047278
rdf:type
n3:Context
rdf:value
For FAAP24, we utilized a FANCM−/− DT40 cell line expressing a FANCM mutant lacking the C-terminal ERCC4-like nuclease domain FANCM-ΔC [>>36<<] (Figure 2a).
n3:mentions
n2:19465393
Subject Item
_:vb59047279
rdf:type
n3:Context
rdf:value
This domain has been shown to directly interact with FAAP24 to form a heterodimer that has ssDNA binding activity but no nuclease activity, and deletion of the domain abolishes FANCM-FAAP24 association [>>22<<]. We found that these FANCM mutant cells (FANCM-ΔC) formed FANCM foci in response to MMC, but the percentage of cells with the foci was lower than that of wild-type cells (Figure 2b and c), suggesting that FANCM recruitment depends on its
n3:mentions
n2:17289582
Subject Item
_:vb59047280
rdf:type
n3:Context
rdf:value
MHF binds to a motif adjacent to the helicase domain of FANCM (Figure 2a); and one of its subunits, MHF1, has been inactivated in DT40 cells [>>23<<]. We found that the percentage of MHF1−/− cells that formed FANCM foci in response to MMC was lower when compared with that of the wild-type cells (about 8% vs 60%; Supplementary Figure S2A and B), suggesting that MHF may be needed for
n3:mentions
n2:20347428
Subject Item
_:vb59047281
rdf:type
n3:Context
rdf:value
However, MHF is known to have at least two different effects on FANCM: it stabilizes FANCM protein, and provides a DNA-binding surface to help FANCM to bind DNA [>>23<<, 44]. To distinguish these possibilities, we rescued MHF1−/− cells with an MHF1 point mutant A that is defective in DNA-binding but can stabilize FANCM [23]. We found that this mutant largely rescued FANCM recruitment to stalled forks
n3:mentions
n2:20347428
Subject Item
_:vb59047282
rdf:type
n3:Context
rdf:value
However, MHF is known to have at least two different effects on FANCM: it stabilizes FANCM protein, and provides a DNA-binding surface to help FANCM to bind DNA [23, >>44<<]. To distinguish these possibilities, we rescued MHF1−/− cells with an MHF1 point mutant A that is defective in DNA-binding but can stabilize FANCM [23]. We found that this mutant largely rescued FANCM recruitment to stalled forks when
n3:mentions
n2:24699063
Subject Item
_:vb59047283
rdf:type
n3:Context
rdf:value
To distinguish these possibilities, we rescued MHF1−/− cells with an MHF1 point mutant A that is defective in DNA-binding but can stabilize FANCM [>>23<<]. We found that this mutant largely rescued FANCM recruitment to stalled forks when compared with the MHF1-wild-type protein (Supplementary Figure S2A–C), indicating that the observed reduction of FANCM foci is due to reduced FANCM
n3:mentions
n2:20347428
Subject Item
_:vb59047284
rdf:type
n3:Context
rdf:value
Previous studies have shown that recruitment of BLM to stalled forks requires its interaction with FANCM [>>35<<]. The findings prompted us to investigate whether recruitment of FANCM to stalled forks reciprocally depends on its interaction with the BLM complex.
n3:mentions
n2:20064461
Subject Item
_:vb59047285
rdf:type
n3:Context
rdf:value
FANCM interacts with BLM complex through an interface consisting of residues from the MM2 motif of FANCM, RMI1 and RMI2 (Figures 2a and 3a) [>>35<<, 43]. It was shown that a single point mutation within RMI2, K121A, disrupts this interface, leading to dissociation between FANCM and BLM complex [43]. We found that the percentage of RMI2−/− DT40 cells that form FANCM foci in response
n3:mentions
n2:20064461
Subject Item
_:vb59047286
rdf:type
n3:Context
rdf:value
FANCM interacts with BLM complex through an interface consisting of residues from the MM2 motif of FANCM, RMI1 and RMI2 (Figures 2a and 3a) [35, >>43<<]. It was shown that a single point mutation within RMI2, K121A, disrupts this interface, leading to dissociation between FANCM and BLM complex [43]. We found that the percentage of RMI2−/− DT40 cells that form FANCM foci in response to
n3:mentions
n2:22392978
Subject Item
_:vb59047287
rdf:type
n3:Context
rdf:value
It was shown that a single point mutation within RMI2, K121A, disrupts this interface, leading to dissociation between FANCM and BLM complex [>>43<<]. We found that the percentage of RMI2−/− DT40 cells that form FANCM foci in response to MMC was drastically reduced when compared with that of the wild-type DT40 cells (Figure 3b and c); this reduction was largely rescued when human
n3:mentions
n2:22392978
Subject Item
_:vb59047288
rdf:type
n3:Context
rdf:value
FANCM directly interacts with the FA core complex (Figure 2a), and it is also required for recruitment of the FA core complex to chromatin and stalled forks [>>19<<, 35, 46, 47]. We investigated whether the FA core complex is reciprocally needed for FANCM recruitment to stalled forks.
n3:mentions
n2:16116422
Subject Item
_:vb59047289
rdf:type
n3:Context
rdf:value
FANCM directly interacts with the FA core complex (Figure 2a), and it is also required for recruitment of the FA core complex to chromatin and stalled forks [19, >>35<<, 46, 47]. We investigated whether the FA core complex is reciprocally needed for FANCM recruitment to stalled forks.
n3:mentions
n2:20064461
Subject Item
_:vb59047290
rdf:type
n3:Context
rdf:value
FANCM directly interacts with the FA core complex (Figure 2a), and it is also required for recruitment of the FA core complex to chromatin and stalled forks [19, 35, >>46<<, 47]. We investigated whether the FA core complex is reciprocally needed for FANCM recruitment to stalled forks.
n3:mentions
n2:26430909
Subject Item
_:vb59047291
rdf:type
n3:Context
rdf:value
FANCM directly interacts with the FA core complex (Figure 2a), and it is also required for recruitment of the FA core complex to chromatin and stalled forks [19, 35, 46, >>47<<]. We investigated whether the FA core complex is reciprocally needed for FANCM recruitment to stalled forks.
n3:mentions
n2:18174376
Subject Item
_:vb59047292
rdf:type
n3:Context
rdf:value
It was shown that the subunit of the FA core complex that directly interacts with FANCM is FANCF [>>35<<]. However, FANCF-knockout DT40 cell line is currently not available. Thus, we chose to examine FANCM recruitment in DT40 cells inactivated of two FA core complex subunits, FANCA and FANCL, because both have been shown to be crucial for
n3:mentions
n2:20064461
Subject Item
_:vb59047293
rdf:type
n3:Context
rdf:value
Thus, we chose to examine FANCM recruitment in DT40 cells inactivated of two FA core complex subunits, FANCA and FANCL, because both have been shown to be crucial for stability and assembly of the FA core complex [>>19<<, 21, 48, 49].
n3:mentions
n2:16116422
Subject Item
_:vb59047294
rdf:type
n3:Context
rdf:value
Thus, we chose to examine FANCM recruitment in DT40 cells inactivated of two FA core complex subunits, FANCA and FANCL, because both have been shown to be crucial for stability and assembly of the FA core complex [19, >>21<<, 48, 49]. FANCA inactivation destabilizes FANCG and also impairs nuclear localization of FANCL, FANCB and FAAP100; whereas FANCL inactivation destabilizes FAAP100, and also impairs the association among FANCF, FANCA and FANCG [19, 21, 48,
n3:mentions
n2:17396147
Subject Item
_:vb59047295
rdf:type
n3:Context
rdf:value
Thus, we chose to examine FANCM recruitment in DT40 cells inactivated of two FA core complex subunits, FANCA and FANCL, because both have been shown to be crucial for stability and assembly of the FA core complex [19, 21, >>48<<, 49]. FANCA inactivation destabilizes FANCG and also impairs nuclear localization of FANCL, FANCB and FAAP100; whereas FANCL inactivation destabilizes FAAP100, and also impairs the association among FANCF, FANCA and FANCG [19, 21, 48, 49].
n3:mentions
n2:16116434
Subject Item
_:vb59047296
rdf:type
n3:Context
rdf:value
Thus, we chose to examine FANCM recruitment in DT40 cells inactivated of two FA core complex subunits, FANCA and FANCL, because both have been shown to be crucial for stability and assembly of the FA core complex [19, 21, 48, >>49<<]. FANCA inactivation destabilizes FANCG and also impairs nuclear localization of FANCL, FANCB and FAAP100; whereas FANCL inactivation destabilizes FAAP100, and also impairs the association among FANCF, FANCA and FANCG [19, 21, 48, 49]. We
n3:mentions
n2:16720839
Subject Item
_:vb59047297
rdf:type
n3:Context
rdf:value
FANCA inactivation destabilizes FANCG and also impairs nuclear localization of FANCL, FANCB and FAAP100; whereas FANCL inactivation destabilizes FAAP100, and also impairs the association among FANCF, FANCA and FANCG [>>19<<, 21, 48, 49].
n3:mentions
n2:16116422
Subject Item
_:vb59047298
rdf:type
n3:Context
rdf:value
FANCA inactivation destabilizes FANCG and also impairs nuclear localization of FANCL, FANCB and FAAP100; whereas FANCL inactivation destabilizes FAAP100, and also impairs the association among FANCF, FANCA and FANCG [19, >>21<<, 48, 49]. We found that the percentage of FANCA−/− and FANCL−/− cells that form FANCM foci in response to MMC was indistinguishable from that of the wild-type cells (Figure 4a and b), suggesting that FANCM recruitment to stalled forks is
n3:mentions
n2:17396147
Subject Item
_:vb59047299
rdf:type
n3:Context
rdf:value
FANCA inactivation destabilizes FANCG and also impairs nuclear localization of FANCL, FANCB and FAAP100; whereas FANCL inactivation destabilizes FAAP100, and also impairs the association among FANCF, FANCA and FANCG [19, 21, >>48<<, 49]. We found that the percentage of FANCA−/− and FANCL−/− cells that form FANCM foci in response to MMC was indistinguishable from that of the wild-type cells (Figure 4a and b), suggesting that FANCM recruitment to stalled forks is
n3:mentions
n2:16116434
Subject Item
_:vb59047300
rdf:type
n3:Context
rdf:value
FANCA inactivation destabilizes FANCG and also impairs nuclear localization of FANCL, FANCB and FAAP100; whereas FANCL inactivation destabilizes FAAP100, and also impairs the association among FANCF, FANCA and FANCG [19, 21, 48, >>49<<]. We found that the percentage of FANCA−/− and FANCL−/− cells that form FANCM foci in response to MMC was indistinguishable from that of the wild-type cells (Figure 4a and b), suggesting that FANCM recruitment to stalled forks is
n3:mentions
n2:16720839
Subject Item
_:vb59047301
rdf:type
n3:Context
rdf:value
FANCM is hyperphosphorylated in response to DNA damage and replication stress; and this phosphorylation has been reported to depend on cell cycle checkpoint kinases, ATR and ATM [>>19<<, 50, 51]. We found that, when DT40 cells were treated with an ATR kinase inhibitor, VE821, the percentage of cells that form FANCM foci in response to MMC was decreased by about 5-fold (Figure 4d and e), suggesting that FANCM recruitment
n3:mentions
n2:16116422
Subject Item
_:vb59047302
rdf:type
n3:Context
rdf:value
FANCM is hyperphosphorylated in response to DNA damage and replication stress; and this phosphorylation has been reported to depend on cell cycle checkpoint kinases, ATR and ATM [19, >>50<<, 51]. We found that, when DT40 cells were treated with an ATR kinase inhibitor, VE821, the percentage of cells that form FANCM foci in response to MMC was decreased by about 5-fold (Figure 4d and e), suggesting that FANCM recruitment to
n3:mentions
n2:19633289
Subject Item
_:vb59047303
rdf:type
n3:Context
rdf:value
FANCM is hyperphosphorylated in response to DNA damage and replication stress; and this phosphorylation has been reported to depend on cell cycle checkpoint kinases, ATR and ATM [19, 50, >>51<<]. We found that, when DT40 cells were treated with an ATR kinase inhibitor, VE821, the percentage of cells that form FANCM foci in response to MMC was decreased by about 5-fold (Figure 4d and e), suggesting that FANCM recruitment to
n3:mentions
n2:23698467
Subject Item
_:vb59047304
rdf:type
n3:Context
rdf:value
recruitment of FANCM to stalled forks depends on ATR, but not on ATM, which is parallel to the earlier results that ATR-dependent phosphorylation of FANCM is required for its recruitment to sites of ICLs regardless of cell cycle stages [>>51<<].
n3:mentions
n2:23698467
Subject Item
_:vb59047305
rdf:type
n3:Context
rdf:value
The data are consistent with the earlier findings that ATR is mainly activated by replication stress, whereas ATM by double-strand breaks [>>52<<].
n3:mentions
n2:20965415
Subject Item
_:vb59047306
rdf:type
n3:Context
rdf:value
FANCM hyperphosphorylation in response to replication stress requires its association with BLM complex, using SDS polyacrylamide gel electrophoresis that can distinguish the hyperphosphorylated from hypophosphorylated forms of FANCM [>>19<<, 51]. Consistent with earlier findings, FANCM in wild-type DT40 cells treated with MMC for increasing lengths of time exhibited decreasing mobility on SDS gels (Figure 5a), indicating that more FANCM became hyperphosphorylated when more
n3:mentions
n2:16116422
Subject Item
_:vb59047307
rdf:type
n3:Context
rdf:value
hyperphosphorylation in response to replication stress requires its association with BLM complex, using SDS polyacrylamide gel electrophoresis that can distinguish the hyperphosphorylated from hypophosphorylated forms of FANCM [19, >>51<<]. Consistent with earlier findings, FANCM in wild-type DT40 cells treated with MMC for increasing lengths of time exhibited decreasing mobility on SDS gels (Figure 5a), indicating that more FANCM became hyperphosphorylated when more DT40
n3:mentions
n2:23698467
Subject Item
_:vb59047308
rdf:type
n3:Context
rdf:value
Notably, the decrease of FANCM mobility was not restored by re-introduction of the RMI2-K121A mutant, which disrupts FANCM–BLM complex association (Figure 5a) [>>43<<]. These results demonstrate that replication stress-induced FANCM hypersphosphorylation depends on RMI2-mediated interaction between FANCM and BLM complex.
n3:mentions
n2:22392978
Subject Item
_:vb59047309
rdf:type
n3:Context
rdf:value
FANCM is known to exclusively associate with chromatin, and this association depends on FAAP24 and MHF [>>23<<, 47]. Our findings that BLM complex is needed for MMC-induced FANCM hyperphosphorylation and recruitment to stalled replication forks led us to investigate whether the BLM complex is also required for chromatin association of FANCM.
n3:mentions
n2:20347428
Subject Item
_:vb59047310
rdf:type
n3:Context
rdf:value
FANCM is known to exclusively associate with chromatin, and this association depends on FAAP24 and MHF [23, >>47<<]. Our findings that BLM complex is needed for MMC-induced FANCM hyperphosphorylation and recruitment to stalled replication forks led us to investigate whether the BLM complex is also required for chromatin association of FANCM.
n3:mentions
n2:18174376
Subject Item
_:vb59047311
rdf:type
n3:Context
rdf:value
Mutation in FANCM phosphorylation sites has been shown to disrupt FANCD2 monoubiquitination and foci formation in response to replication stress [>>51<<], both of which are key steps of the FA pathway. Because RMI2 mutant cells lacking FANCM–BLM association are defective in FANCM hyperphophorylation, we hypothesize that the same cells may also be impaired in the FA pathway.
n3:mentions
n2:23698467
Subject Item
_:vb59047312
rdf:type
n3:Context
rdf:value
Previous studies have reported that FANCD2 monoubiquitination was modestly reduced in BLM-deficient human cells [>>53<<] and BLM−/− chicken DT40 cells in response to drugs that induce ICLs [36]. We performed the experiments in BLM−/− DT40 cells and observed a similar reduction (Figure 5f and Supplementary Figure S1A).
n3:mentions
n2:27083049
Subject Item
_:vb59047313
rdf:type
n3:Context
rdf:value
Previous studies have reported that FANCD2 monoubiquitination was modestly reduced in BLM-deficient human cells [53] and BLM−/− chicken DT40 cells in response to drugs that induce ICLs [>>36<<]. We performed the experiments in BLM−/− DT40 cells and observed a similar reduction (Figure 5f and Supplementary Figure S1A).
n3:mentions
n2:19465393
Subject Item
_:vb59047314
rdf:type
n3:Context
rdf:value
FANCM has a major role in promoting replication traverse of ICLs [>>30<<]. Because RMI2-mediated FANCM–BLM association is required for FANCM hyperphosphorylation and recruitment to stalled forks, we studied whether this association is needed for replication traverse of ICLs using the same assay described
n3:mentions
n2:24207054
Subject Item
_:vb59047315
rdf:type
n3:Context
rdf:value
RMI2-mediated FANCM–BLM association is required for FANCM hyperphosphorylation and recruitment to stalled forks, we studied whether this association is needed for replication traverse of ICLs using the same assay described previously [>>30<<]. Briefly, DT40 cells of different genotypes were first treated with Dig-TMP (digoxigenin-tagged trimethylpsoralen) and ultraviolet A to induce ICLs; and then were sequentially pulsed with CIdU and IdU to label replication tracks (Figure
n3:mentions
n2:24207054
Subject Item
_:vb59047316
rdf:type
n3:Context
rdf:value
Earlier studies have shown that the two proteins work in the same pathway to suppress SCEs and to promote cellular resistance to ICLs [>>36<<]. We studied how they act in the replication traverse pathway. Consistent with earlier findings [30], DT40 cells carrying a knock-in mutation of the FANCM helicase domain, D203A, displayed a lower level of traverse than wild-type DT40
n3:mentions
n2:19465393
Subject Item
_:vb59047317
rdf:type
n3:Context
rdf:value
Consistent with earlier findings [>>30<<], DT40 cells carrying a knock-in mutation of the FANCM helicase domain, D203A, displayed a lower level of traverse than wild-type DT40 cells (about 20% vs 50%); and this level was comparable to that of BLM−/− cells (Figure 6d).
n3:mentions
n2:24207054
Subject Item
_:vb59047318
rdf:type
n3:Context
rdf:value
BLM and FANCM have been shown to suppress new origin firing in human and/or chicken DT40 cells [>>15<<, 30, 54]. We obtained similar findings in our analyses for FANCM-D203A mutant cells (Figure 6d), but we did not observe an obvious increase of new origin firing in BLM−/− cells.
n3:mentions
n2:17603497
Subject Item
_:vb59047319
rdf:type
n3:Context
rdf:value
BLM and FANCM have been shown to suppress new origin firing in human and/or chicken DT40 cells [15, >>30<<, 54]. We obtained similar findings in our analyses for FANCM-D203A mutant cells (Figure 6d), but we did not observe an obvious increase of new origin firing in BLM−/− cells.
n3:mentions
n2:24207054
Subject Item
_:vb59047320
rdf:type
n3:Context
rdf:value
BLM and FANCM have been shown to suppress new origin firing in human and/or chicken DT40 cells [15, 30, >>54<<]. We obtained similar findings in our analyses for FANCM-D203A mutant cells (Figure 6d), but we did not observe an obvious increase of new origin firing in BLM−/− cells.
n3:mentions
n2:25794620
Subject Item
_:vb59047321
rdf:type
n3:Context
rdf:value
One possible explanation for this difference is that we used a DNA crosslinking drug to induce replication stress, whereas the prior studies used non-crosslinking drugs [>>15<<]. BLM may only be needed for suppressing new origin firing for the latter drugs.
n3:mentions
n2:17603497
Subject Item
_:vb59047322
rdf:type
n6:Section
dc:title
discussion
n6:contains
_:vb59047324 _:vb59047325 _:vb59047326 _:vb59047327 _:vb59047323 _:vb59047340 _:vb59047341 _:vb59047342 _:vb59047343 _:vb59047336 _:vb59047337 _:vb59047338 _:vb59047339 _:vb59047332 _:vb59047333 _:vb59047334 _:vb59047335 _:vb59047328 _:vb59047329 _:vb59047330 _:vb59047331 _:vb59047352 _:vb59047353 _:vb59047354 _:vb59047355 _:vb59047348 _:vb59047349 _:vb59047350 _:vb59047351 _:vb59047344 _:vb59047345 _:vb59047346 _:vb59047347
Subject Item
_:vb59047323
rdf:type
n3:Context
rdf:value
First, the FANCM recruitment depends on its own translocase activity, which is necessary for replication traverse of ICLs [>>30<<]. Thus, targeting FANCM to stalled forks could be a new mechanism by which FANCM translocase facilitates the traverse of ICLs. Possibly, translocating FANCM on dsDNA may enable FANCM to scan large regions of genomes and locate the stalled
n3:mentions
n2:24207054
Subject Item
_:vb59047324
rdf:type
n3:Context
rdf:value
Second, the FANCM recruitment depends on ATR, which is known to hyperphosphorylate FANCM [>>51<<] in response to replication stress.
n3:mentions
n2:23698467
Subject Item
_:vb59047325
rdf:type
n3:Context
rdf:value
This feature of FANCM resembles that of FA core complex [>>55<<], FANCD2 [56, 57] and BLM [58], the recruitment of which also depends on ATR.
n3:mentions
n2:19109555
Subject Item
_:vb59047326
rdf:type
n3:Context
rdf:value
This feature of FANCM resembles that of FA core complex [55], FANCD2 [>>56<<, 57] and BLM [58], the recruitment of which also depends on ATR.
n3:mentions
n2:14988723
Subject Item
_:vb59047327
rdf:type
n3:Context
rdf:value
This feature of FANCM resembles that of FA core complex [55], FANCD2 [56, >>57<<] and BLM [58], the recruitment of which also depends on ATR.
n3:mentions
n2:16943440
Subject Item
_:vb59047328
rdf:type
n3:Context
rdf:value
This feature of FANCM resembles that of FA core complex [55], FANCD2 [56, 57] and BLM [>>58<<], the recruitment of which also depends on ATR.
n3:mentions
n2:15364958
Subject Item
_:vb59047329
rdf:type
n3:Context
rdf:value
Our data thus suggest that FANCM recruitment occurs downstream of ATR, which is similar to that of the FA core complex [>>46<<] (Figure 7).
n3:mentions
n2:26430909
Subject Item
_:vb59047330
rdf:type
n3:Context
rdf:value
Several independent studies have shown that FANCM and its partner, FAAP24, are required for full ATR activation in response to replication stress [>>31<<, 34, 40, 59]. Conversely, other studies, including this one, have shown that FANCM is a downstream substrate of ATR [50, 51].
n3:mentions
n2:18995830
Subject Item
_:vb59047331
rdf:type
n3:Context
rdf:value
Several independent studies have shown that FANCM and its partner, FAAP24, are required for full ATR activation in response to replication stress [31, >>34<<, 40, 59]. Conversely, other studies, including this one, have shown that FANCM is a downstream substrate of ATR [50, 51].
n3:mentions
n2:20670894
Subject Item
_:vb59047332
rdf:type
n3:Context
rdf:value
Several independent studies have shown that FANCM and its partner, FAAP24, are required for full ATR activation in response to replication stress [31, 34, >>40<<, 59]. Conversely, other studies, including this one, have shown that FANCM is a downstream substrate of ATR [50, 51].
n3:mentions
n2:20057355
Subject Item
_:vb59047333
rdf:type
n3:Context
rdf:value
Several independent studies have shown that FANCM and its partner, FAAP24, are required for full ATR activation in response to replication stress [31, 34, 40, >>59<<]. Conversely, other studies, including this one, have shown that FANCM is a downstream substrate of ATR [50, 51].
n3:mentions
n2:23333308
Subject Item
_:vb59047334
rdf:type
n3:Context
rdf:value
Conversely, other studies, including this one, have shown that FANCM is a downstream substrate of ATR [>>50<<, 51]. Together, these data imply that ATR and FANCM may constitute a positive feedback loop that mutually activates each other. This loop may not only sense and transduce the stress signal, but also amplifies it, to elicit a stronger
n3:mentions
n2:19633289
Subject Item
_:vb59047335
rdf:type
n3:Context
rdf:value
Conversely, other studies, including this one, have shown that FANCM is a downstream substrate of ATR [50, >>51<<]. Together, these data imply that ATR and FANCM may constitute a positive feedback loop that mutually activates each other. This loop may not only sense and transduce the stress signal, but also amplifies it, to elicit a stronger response
n3:mentions
n2:23698467
Subject Item
_:vb59047336
rdf:type
n3:Context
rdf:value
We hypothesize that ATR is likely to be activated first, based on the fact that ATR is essential for viability of mouse and many cell lines [>>60<<], whereas FANCM is non-essential [61].
n3:mentions
n2:10691732
Subject Item
_:vb59047337
rdf:type
n3:Context
rdf:value
We hypothesize that ATR is likely to be activated first, based on the fact that ATR is essential for viability of mouse and many cell lines [60], whereas FANCM is non-essential [>>61<<]. Thus, there may exist FANCM-independent pathways that can activate ATR.
n3:mentions
n2:19561169
Subject Item
_:vb59047338
rdf:type
n3:Context
rdf:value
Because the FA core complex and FANCM can be co-purified in a highly stable complex [>>7<<, 19, 23], they are likely to be co-recruited to stalled forks.
n3:mentions
n2:12724401
Subject Item
_:vb59047339
rdf:type
n3:Context
rdf:value
Because the FA core complex and FANCM can be co-purified in a highly stable complex [7, >>19<<, 23], they are likely to be co-recruited to stalled forks.
n3:mentions
n2:16116422
Subject Item
_:vb59047340
rdf:type
n3:Context
rdf:value
Because the FA core complex and FANCM can be co-purified in a highly stable complex [7, 19, >>23<<], they are likely to be co-recruited to stalled forks.
n3:mentions
n2:20347428
Subject Item
_:vb59047341
rdf:type
n3:Context
rdf:value
Notably, the FANCM recruitment depends on its DNA-binding partners, FAAP24 and BLM complex; but not on the FA core complex, which lacks obvious DNA-binding activity [>>7<<]. FAAP24 is known to stimulate FANCM to bind DNA in vitro, and is required for FANCM to localize to chromatin and damaged DNA in vivo [22, 47], so that its contribution to FANCM recruitment was to be expected. However, the roles of BLM
n3:mentions
n2:12724401
Subject Item
_:vb59047342
rdf:type
n3:Context
rdf:value
FAAP24 is known to stimulate FANCM to bind DNA in vitro, and is required for FANCM to localize to chromatin and damaged DNA in vivo [>>22<<, 47], so that its contribution to FANCM recruitment was to be expected.
n3:mentions
n2:17289582
Subject Item
_:vb59047343
rdf:type
n3:Context
rdf:value
FAAP24 is known to stimulate FANCM to bind DNA in vitro, and is required for FANCM to localize to chromatin and damaged DNA in vivo [22, >>47<<], so that its contribution to FANCM recruitment was to be expected.
n3:mentions
n2:18174376
Subject Item
_:vb59047344
rdf:type
n3:Context
rdf:value
Because BLM can be purified as a stable complex with FANCM and FA core complex [>>7<<, 23], and FANCM can simultaneously interact with both BLM complex and FA core complex using two separate motifs [35, 62], our findings imply that BLM is co-recruited with FANCM and FA core complex to stalled forks as a super-complex
n3:mentions
n2:12724401
Subject Item
_:vb59047345
rdf:type
n3:Context
rdf:value
Because BLM can be purified as a stable complex with FANCM and FA core complex [7, >>23<<], and FANCM can simultaneously interact with both BLM complex and FA core complex using two separate motifs [35, 62], our findings imply that BLM is co-recruited with FANCM and FA core complex to stalled forks as a super-complex (Figure
n3:mentions
n2:20347428
Subject Item
_:vb59047346
rdf:type
n3:Context
rdf:value
Because BLM can be purified as a stable complex with FANCM and FA core complex [7, 23], and FANCM can simultaneously interact with both BLM complex and FA core complex using two separate motifs [>>35<<, 62], our findings imply that BLM is co-recruited with FANCM and FA core complex to stalled forks as a super-complex (Figure 7).
n3:mentions
n2:20064461
Subject Item
_:vb59047347
rdf:type
n3:Context
rdf:value
Because BLM can be purified as a stable complex with FANCM and FA core complex [7, 23], and FANCM can simultaneously interact with both BLM complex and FA core complex using two separate motifs [35, >>62<<], our findings imply that BLM is co-recruited with FANCM and FA core complex to stalled forks as a super-complex (Figure 7).
n3:mentions
n2:20826341
Subject Item
_:vb59047348
rdf:type
n3:Context
rdf:value
Consistent with this notion, earlier studies have shown that BLM recruitment requires its association with FANCM [>>35<<]. Moreover, FA core complex recruitment depends on FANCM [46]. Furthermore, our data showed that FANCM recruitment reciprocally requires its association with BLM complex. This mutual dependence supports their co-recruitment: when a
n3:mentions
n2:20064461
Subject Item
_:vb59047349
rdf:type
n3:Context
rdf:value
Moreover, FA core complex recruitment depends on FANCM [>>46<<]. Furthermore, our data showed that FANCM recruitment reciprocally requires its association with BLM complex.
n3:mentions
n2:26430909
Subject Item
_:vb59047350
rdf:type
n3:Context
rdf:value
partners, MHF resembles FANCM in that both are required for optimal execution of the FA repair and replication traverse pathways for ICLs, whereas the FA core complex is needed only for the former but not for the latter (See Figure 7) [>>23<<, 24, 30]. BLM has been previously implicated in the FA pathway and repair of ICLs [36, 53, 63–65].
n3:mentions
n2:20347428
Subject Item
_:vb59047351
rdf:type
n3:Context
rdf:value
MHF resembles FANCM in that both are required for optimal execution of the FA repair and replication traverse pathways for ICLs, whereas the FA core complex is needed only for the former but not for the latter (See Figure 7) [23, >>24<<, 30]. BLM has been previously implicated in the FA pathway and repair of ICLs [36, 53, 63–65].
n3:mentions
n2:20347429
Subject Item
_:vb59047352
rdf:type
n3:Context
rdf:value
MHF resembles FANCM in that both are required for optimal execution of the FA repair and replication traverse pathways for ICLs, whereas the FA core complex is needed only for the former but not for the latter (See Figure 7) [23, 24, >>30<<]. BLM has been previously implicated in the FA pathway and repair of ICLs [36, 53, 63–65].
n3:mentions
n2:24207054
Subject Item
_:vb59047353
rdf:type
n3:Context
rdf:value
BLM has been previously implicated in the FA pathway and repair of ICLs [>>36<<, 53, 63–65].
n3:mentions
n2:19465393
Subject Item
_:vb59047354
rdf:type
n3:Context
rdf:value
BLM has been previously implicated in the FA pathway and repair of ICLs [36, >>53<<, 63–65]. This study uncovered a new role of the BLM complex—it works with FANCM in the traverse pathway (Figure 6). Importantly, our data demonstrate that BLM complex may coordinate the two pathways at different steps using different
n3:mentions
n2:27083049
Subject Item
_:vb59047355
rdf:type
n3:Context
rdf:value
BLM has been previously implicated in the FA pathway and repair of ICLs [36, 53, 63–>>65<<]. This study uncovered a new role of the BLM complex—it works with FANCM in the traverse pathway (Figure 6). Importantly, our data demonstrate that BLM complex may coordinate the two pathways at different steps using different mechanisms
n3:mentions
n2:7207483 n2:6429525 n2:15616572
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_:vb620096278
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6
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5
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