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PMC0
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10.1093%2Fnar%2Fgkn995
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introduction
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Fanconi anemia (FA) is a multigenic disease associated with bone marrow failure and cancer susceptibility, particularly acute myelogenous leukemia (AML) and squamous cell carcinoma of the head and neck (>>1<<,2). FA cells display chromosome fragility, characterized by chromosome breakage and the formation of radial chromosomes, in response to DNA interstrand crosslinkers such as mitomycin C (MMC).
n2:mentions
n3:12518367
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_:vb4574200
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Fanconi anemia (FA) is a multigenic disease associated with bone marrow failure and cancer susceptibility, particularly acute myelogenous leukemia (AML) and squamous cell carcinoma of the head and neck (1,>>2<<). FA cells display chromosome fragility, characterized by chromosome breakage and the formation of radial chromosomes, in response to DNA interstrand crosslinkers such as mitomycin C (MMC).
n2:mentions
n3:16493006
Subject Item
_:vb4574201
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rdf:value
FA cells are also hypersensitive to MMC (2–>>4<<). Together, these results suggest that Fanconi anemia is linked to a defect in the cellular response to DNA damage.
n2:mentions
n3:16132046 n3:16493006 n3:11239454
Subject Item
_:vb4574202
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The genes for 13 FA subtypes (A, B, C, D1, D2, E, F, G, I, J, L and M and N) have been identified (>>2<<,4,5). The encoded FA proteins cooperate in the FA pathway (3). Eight of the FA proteins (A, B, C, E, F, G, L and M) assemble into a nuclear core complex that is required for the monoubiquitination of FANCD2 and FANCI (2–4).
n2:mentions
n3:16493006
Subject Item
_:vb4574203
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n2:Context
rdf:value
The genes for 13 FA subtypes (A, B, C, D1, D2, E, F, G, I, J, L and M and N) have been identified (2,>>4<<,5). The encoded FA proteins cooperate in the FA pathway (3). Eight of the FA proteins (A, B, C, E, F, G, L and M) assemble into a nuclear core complex that is required for the monoubiquitination of FANCD2 and FANCI (2–4).
n2:mentions
n3:16132046
Subject Item
_:vb4574204
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n2:Context
rdf:value
The genes for 13 FA subtypes (A, B, C, D1, D2, E, F, G, I, J, L and M and N) have been identified (2,4,>>5<<). The encoded FA proteins cooperate in the FA pathway (3). Eight of the FA proteins (A, B, C, E, F, G, L and M) assemble into a nuclear core complex that is required for the monoubiquitination of FANCD2 and FANCI (2–4).
n2:mentions
n3:17488615
Subject Item
_:vb4574205
rdf:type
n2:Context
rdf:value
The encoded FA proteins cooperate in the FA pathway (>>3<<). Eight of the FA proteins (A, B, C, E, F, G, L and M) assemble into a nuclear core complex that is required for the monoubiquitination of FANCD2 and FANCI (2–4).
n2:mentions
n3:11239454
Subject Item
_:vb4574206
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Eight of the FA proteins (A, B, C, E, F, G, L and M) assemble into a nuclear core complex that is required for the monoubiquitination of FANCD2 and FANCI (2–>>4<<). Monoubiquitination of FANCD2 is critical for the normal function of DNA damage responses. A non-ubiquitinable mutant of FANCD2, mutated at the site of ubiquitin conjugation, is completely incapable of restoring MMC resistance to
n2:mentions
n3:16132046 n3:16493006 n3:11239454
Subject Item
_:vb4574207
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A non-ubiquitinable mutant of FANCD2, mutated at the site of ubiquitin conjugation, is completely incapable of restoring MMC resistance to FANCD2-deficient cells (>>3<<,6,7). In contrast, a non-ubiquitinable mutant of FANCI partially restores MMC resistance in FANCI-deficient cells (8).
n2:mentions
n3:11239454
Subject Item
_:vb4574208
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A non-ubiquitinable mutant of FANCD2, mutated at the site of ubiquitin conjugation, is completely incapable of restoring MMC resistance to FANCD2-deficient cells (3,>>6<<,7). In contrast, a non-ubiquitinable mutant of FANCI partially restores MMC resistance in FANCI-deficient cells (8).
n2:mentions
n3:12086603
Subject Item
_:vb4574209
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rdf:value
A non-ubiquitinable mutant of FANCD2, mutated at the site of ubiquitin conjugation, is completely incapable of restoring MMC resistance to FANCD2-deficient cells (3,6,>>7<<). In contrast, a non-ubiquitinable mutant of FANCI partially restores MMC resistance in FANCI-deficient cells (8).
n2:mentions
n3:15454491
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In contrast, a non-ubiquitinable mutant of FANCI partially restores MMC resistance in FANCI-deficient cells (>>8<<).
n2:mentions
n3:17412408
Subject Item
_:vb4574211
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n2:Context
rdf:value
Monoubiquitination of FANCD2 is required for the assembly of this protein into nuclear foci during an unperturbed S phase or in response to DNA damage (>>3<<,9). Consistent with a role for FANCD2 in DNA damage responses, FANCD2 foci colocalize with BRCA1 and RAD51 foci (9).
n2:mentions
n3:11239454
Subject Item
_:vb4574212
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n2:Context
rdf:value
Monoubiquitination of FANCD2 is required for the assembly of this protein into nuclear foci during an unperturbed S phase or in response to DNA damage (3,>>9<<). Consistent with a role for FANCD2 in DNA damage responses, FANCD2 foci colocalize with BRCA1 and RAD51 foci (9).
n2:mentions
n3:12239151
Subject Item
_:vb4574213
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n2:Context
rdf:value
Consistent with a role for FANCD2 in DNA damage responses, FANCD2 foci colocalize with BRCA1 and RAD51 foci (>>9<<). The ATR checkpoint kinase, along with the FA nuclear core complex, is involved in the regulation of FANCD2 monoubiquitination and the assembly of FANCD2 foci in response to DNA damage (10).
n2:mentions
n3:12239151
Subject Item
_:vb4574214
rdf:type
n2:Context
rdf:value
The ATR checkpoint kinase, along with the FA nuclear core complex, is involved in the regulation of FANCD2 monoubiquitination and the assembly of FANCD2 foci in response to DNA damage (>>10<<).
n2:mentions
n3:15314022
Subject Item
_:vb4574215
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n2:Context
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Telomere dysfunction can occur either through progressive telomere shortening or other changes in telomere structure that leave the chromosome ends unprotected (>>11<<,12). Similar to FA, telomere dysfunction results in chromosome instability, in particular chromosome end fusions and complex rearrangements (11,12).
n2:mentions
n3:12757975
Subject Item
_:vb4574216
rdf:type
n2:Context
rdf:value
Telomere dysfunction can occur either through progressive telomere shortening or other changes in telomere structure that leave the chromosome ends unprotected (11,>>12<<). Similar to FA, telomere dysfunction results in chromosome instability, in particular chromosome end fusions and complex rearrangements (11,12).
n2:mentions
n3:12142527
Subject Item
_:vb4574217
rdf:type
n2:Context
rdf:value
Similar to FA, telomere dysfunction results in chromosome instability, in particular chromosome end fusions and complex rearrangements (>>11<<,12). The shared chromosome instability phenotype suggests that FA proteins could have some role in telomere function.
n2:mentions
n3:12757975
Subject Item
_:vb4574218
rdf:type
n2:Context
rdf:value
Similar to FA, telomere dysfunction results in chromosome instability, in particular chromosome end fusions and complex rearrangements (11,>>12<<). The shared chromosome instability phenotype suggests that FA proteins could have some role in telomere function.
n2:mentions
n3:12142527
Subject Item
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While expression of telomerase is the predominant mechanism of stabilizing telomeres in human tumor cells, the alternative lengthening of telomeres (ALT) pathway is utilized in about 10–15% of human tumors (>>13<<,14). The ALT pathway maintains telomeres through homologous recombination (15,16).
n2:mentions
n3:11121234
Subject Item
_:vb4574220
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rdf:value
While expression of telomerase is the predominant mechanism of stabilizing telomeres in human tumor cells, the alternative lengthening of telomeres (ALT) pathway is utilized in about 10–15% of human tumors (13,>>14<<). The ALT pathway maintains telomeres through homologous recombination (15,16). ALT cells display a corresponding increase in sister chromatid exchanges at telomeres (T-SCE), as compared to non-ALT cells (17,18).
n2:mentions
n3:11850785
Subject Item
_:vb4574221
rdf:type
n2:Context
rdf:value
The ALT pathway maintains telomeres through homologous recombination (>>15<<,16). ALT cells display a corresponding increase in sister chromatid exchanges at telomeres (T-SCE), as compared to non-ALT cells (17,18).
n2:mentions
n3:11101843
Subject Item
_:vb4574222
rdf:type
n2:Context
rdf:value
The ALT pathway maintains telomeres through homologous recombination (15,>>16<<). ALT cells display a corresponding increase in sister chromatid exchanges at telomeres (T-SCE), as compared to non-ALT cells (17,18).
n2:mentions
n3:11919561
Subject Item
_:vb4574223
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n2:Context
rdf:value
ALT cells display a corresponding increase in sister chromatid exchanges at telomeres (T-SCE), as compared to non-ALT cells (>>17<<,18). Importantly, telomeres in ALT cells have a more heterogeneous length and display increased chromosome instability, including breaks, fusions and fragments, as compared to telomerase-expressing cells (19,20).
n2:mentions
n3:17054727
Subject Item
_:vb4574224
rdf:type
n2:Context
rdf:value
ALT cells display a corresponding increase in sister chromatid exchanges at telomeres (T-SCE), as compared to non-ALT cells (17,>>18<<). Importantly, telomeres in ALT cells have a more heterogeneous length and display increased chromosome instability, including breaks, fusions and fragments, as compared to telomerase-expressing cells (19,20).
n2:mentions
n3:15059879
Subject Item
_:vb4574225
rdf:type
n2:Context
rdf:value
Importantly, telomeres in ALT cells have a more heterogeneous length and display increased chromosome instability, including breaks, fusions and fragments, as compared to telomerase-expressing cells (>>19<<,20).
n2:mentions
n3:11439347
Subject Item
_:vb4574226
rdf:type
n2:Context
rdf:value
Importantly, telomeres in ALT cells have a more heterogeneous length and display increased chromosome instability, including breaks, fusions and fragments, as compared to telomerase-expressing cells (19,>>20<<).
n2:mentions
n3:12514102
Subject Item
_:vb4574227
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n2:Context
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Another characteristic of human ALT cells is that promyelocytic leukemia (PML) nuclear bodies (APBs for ALT-associated PML bodies) colocalize with telomeres during late S phase/G2 (21–>>23<<). Other proteins involved in DNA damage responses, such as NBS1 and MRE11 (22), BRCA1 (24), BLM (23,25), RPA (26,27) and SMC5/6 (28), also localize to APBs.
n2:mentions
n3:11082050 n3:15229185 n3:10913111
Subject Item
_:vb4574228
rdf:type
n2:Context
rdf:value
Other proteins involved in DNA damage responses, such as NBS1 and MRE11 (>>22<<), BRCA1 (24), BLM (23,25), RPA (26,27) and SMC5/6 (28), also localize to APBs.
n2:mentions
n3:10913111
Subject Item
_:vb4574229
rdf:type
n2:Context
rdf:value
Other proteins involved in DNA damage responses, such as NBS1 and MRE11 (22), BRCA1 (>>24<<), BLM (23,25), RPA (26,27) and SMC5/6 (28), also localize to APBs.
n2:mentions
n3:12750284
Subject Item
_:vb4574230
rdf:type
n2:Context
rdf:value
Other proteins involved in DNA damage responses, such as NBS1 and MRE11 (22), BRCA1 (24), BLM (>>23<<,25), RPA (26,27) and SMC5/6 (28), also localize to APBs.
n2:mentions
n3:15229185
Subject Item
_:vb4574231
rdf:type
n2:Context
rdf:value
Other proteins involved in DNA damage responses, such as NBS1 and MRE11 (22), BRCA1 (24), BLM (23,>>25<<), RPA (26,27) and SMC5/6 (28), also localize to APBs.
n2:mentions
n3:12444098
Subject Item
_:vb4574232
rdf:type
n2:Context
rdf:value
Other proteins involved in DNA damage responses, such as NBS1 and MRE11 (22), BRCA1 (24), BLM (23,25), RPA (>>26<<,27) and SMC5/6 (28), also localize to APBs.
n2:mentions
n3:10485449
Subject Item
_:vb4574233
rdf:type
n2:Context
rdf:value
Other proteins involved in DNA damage responses, such as NBS1 and MRE11 (22), BRCA1 (24), BLM (23,25), RPA (26,>>27<<) and SMC5/6 (28), also localize to APBs.
n2:mentions
n3:17959650
Subject Item
_:vb4574234
rdf:type
n2:Context
rdf:value
Other proteins involved in DNA damage responses, such as NBS1 and MRE11 (22), BRCA1 (24), BLM (23,25), RPA (26,27) and SMC5/6 (>>28<<), also localize to APBs.
n2:mentions
n3:17589526
Subject Item
_:vb4574235
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The function of FA proteins in DNA damage responses has been largely characterized in non-ALT cells (>>2<<). Here we demonstrate that FANCD2 localizes to telomeres in immortalized telomerase-negative ALT cells, but not in immortalized/transformed lines expressing telomerase.
n2:mentions
n3:16493006
Subject Item
_:vb4574236
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n6:Section
dc:title
materials and methods
n6:contains
_:vb4574237 _:vb4574238 _:vb4574239 _:vb4574244 _:vb4574245 _:vb4574246 _:vb4574247 _:vb4574240 _:vb4574241 _:vb4574242 _:vb4574243 _:vb4574252 _:vb4574253 _:vb4574248 _:vb4574249 _:vb4574250 _:vb4574251
Subject Item
_:vb4574237
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Transformed ALT cell lines (U2OS, GM847 and WI38/VA13) and telomerase-expressing cell lines (HeLa, MCF7 and 293-EBNA) (>>26<<) were cultured in DMEM (Invitrogen) supplemented with 15% fetal bovine serum (Sigma), 100 U/ml Penicillin, 100 µg/ml Streptomycin and 2 mM l-glutamine at 37°C, 5% CO2.
n2:mentions
n3:10485449
Subject Item
_:vb4574238
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For immunolocalization of all other antigens, cells were fixed with 2% paraformaldehyde for 20 min at RT, permeabilized and processed for immunofluorescence microscopy as we have described previously (>>29<<).
n2:mentions
n3:7962060
Subject Item
_:vb4574239
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n2:Context
rdf:value
Following a PBS wash, cells were incubated with primary antibodies to FANCD2 (E35) or TRF1 (TRF78) as described previously (>>29<<). Secondary antibodies were diluted 200-fold. Cells were washed three times with PBS, post-fixed with 3% paraformaldehyde in PBS for 10 min at RT, and then exposed to two 10 min incubations with 70% ethanol at −20°C. Samples were air
n2:mentions
n3:7962060
Subject Item
_:vb4574240
rdf:type
n2:Context
rdf:value
Expression of targeted genes was knocked down by transient expression of siRNAs directed against ATR, FANCA and GFP, as we have described previously (>>10<<). SiRNAs directed against FANCD2 (30) and FANCL (31) were also utilized. Cells were either left untreated or were exposed to 2 mM HU or 0.5 µM mitomycin C for 24 h.
n2:mentions
n3:15314022
Subject Item
_:vb4574241
rdf:type
n2:Context
rdf:value
SiRNAs directed against FANCD2 (>>30<<) and FANCL (31) were also utilized. Cells were either left untreated or were exposed to 2 mM HU or 0.5 µM mitomycin C for 24 h.
n2:mentions
n3:15661754
Subject Item
_:vb4574242
rdf:type
n2:Context
rdf:value
SiRNAs directed against FANCD2 (30) and FANCL (>>31<<) were also utilized. Cells were either left untreated or were exposed to 2 mM HU or 0.5 µM mitomycin C for 24 h.
n2:mentions
n3:12973351
Subject Item
_:vb4574243
rdf:type
n2:Context
rdf:value
The LeGO-G vector (>>32<<) was kindly provided by Kristoffer Weber and Dr Boris Fehse (University Hospital Eppendorf, Hamburg, Germany).
n2:mentions
n3:18362927
Subject Item
_:vb4574244
rdf:type
n2:Context
rdf:value
Virus was produced by transfection of 293T cells with LeGO-G, along with the packaging plasmids pRRE and pRSV-Rev, and pVSV-G (>>32<<). Virus was concentrated by ultracentrifugation and then centrifuged through a 20% sucrose cushion for additional purification. Virus was aliquoted and stored at –80°C. Target cells were transduced 3X, at approximately 12 h intervals,
n2:mentions
n3:18362927
Subject Item
_:vb4574245
rdf:type
n2:Context
rdf:value
Cells were lysed, protein concentrations determined from supernatants, and sample buffer added to combined supernatants and pellets to prepare whole cell lysates as we have described previously (>>29<<). Equivalent amounts of proteins were loaded for each sample, followed by SDS–PAGE (6% polyacrylamide, bis-acrylamide).
n2:mentions
n3:7962060
Subject Item
_:vb4574246
rdf:type
n2:Context
rdf:value
Proteins were transferred to nitrocellulose, blocked, and incubated with primary antibodies as previously described (>>9<<). Antibodies included anti-FANCA (1:1000) generously provided by Dr Maureen Hoatlin (Oregon Health & Sciences University, Portland, OR, USA), anti-FANCD2 (E35, 1:1000) (3), anti-FANCL (1:2000) (31) from Dr Ruhikanta Meetei (Cincinnati
n2:mentions
n3:12239151
Subject Item
_:vb4574247
rdf:type
n2:Context
rdf:value
Antibodies included anti-FANCA (1:1000) generously provided by Dr Maureen Hoatlin (Oregon Health & Sciences University, Portland, OR, USA), anti-FANCD2 (E35, 1:1000) (>>3<<), anti-FANCL (1:
n2:mentions
n3:11239454
Subject Item
_:vb4574248
rdf:type
n2:Context
rdf:value
Antibodies included anti-FANCA (1:1000) generously provided by Dr Maureen Hoatlin (Oregon Health & Sciences University, Portland, OR, USA), anti-FANCD2 (E35, 1:1000) (3), anti-FANCL (1:2000) (>>31<<) from Dr Ruhikanta Meetei (Cincinnati Children's Research Foundation), anti-ATR (1:
n2:mentions
n3:12973351
Subject Item
_:vb4574249
rdf:type
n2:Context
rdf:value
Membranes were washed, incubated with HRP-linked secondary antibodies (Amersham), and signals detected by chemiluminescence (Amersham) as previously described (>>9<<).
n2:mentions
n3:12239151
Subject Item
_:vb4574250
rdf:type
n2:Context
rdf:value
Cells were swollen, fixed, dried onto slides and prepared for hybridization, as described previously (>>33<<). Hybridization mix [70% formamide, 0.06X SSC, 0.2% bovine serum albumin, 0.5 ng/ml yeast tRNA (Sigma) and 0.5 ng/ml Cy3-labeled telomeric peptide nucleic acid (PNA) probe (Applied Biosystems)] was applied and covered with a plastic
n2:mentions
n3:9207107
Subject Item
_:vb4574251
rdf:type
n2:Context
rdf:value
Due to the wide heterogeneity of telomere lengths in ALT cells (>>16<<,19), longer exposure times were utilized to image telomeres in HeLa cells in a linear range.
n2:mentions
n3:11919561
Subject Item
_:vb4574252
rdf:type
n2:Context
rdf:value
Due to the wide heterogeneity of telomere lengths in ALT cells (16,>>19<<), longer exposure times were utilized to image telomeres in HeLa cells in a linear range.
n2:mentions
n3:11439347
Subject Item
_:vb4574253
rdf:type
n2:Context
rdf:value
T-SCE was analyzed by chromosome orientation fluorescence in situ hybridization (CO-FISH) as previously described (>>34<<), with slight modification. Briefly, U2OS or HeLa cells were grown overnight and then incubated with 10 µM bromodeoxyuridine (BrdU) for 16 h, with 1 µg/ml nocodazole added for the last 5 h.
n2:mentions
n3:15258249
Subject Item
_:vb4574254
rdf:type
n6:Section
dc:title
results
n6:contains
_:vb4574292 _:vb4574288 _:vb4574289 _:vb4574290 _:vb4574291 _:vb4574284 _:vb4574285 _:vb4574286 _:vb4574287 _:vb4574280 _:vb4574281 _:vb4574282 _:vb4574283 _:vb4574276 _:vb4574277 _:vb4574278 _:vb4574279 _:vb4574272 _:vb4574273 _:vb4574274 _:vb4574275 _:vb4574268 _:vb4574269 _:vb4574270 _:vb4574271 _:vb4574264 _:vb4574265 _:vb4574266 _:vb4574267 _:vb4574260 _:vb4574261 _:vb4574262 _:vb4574263 _:vb4574256 _:vb4574257 _:vb4574258 _:vb4574259 _:vb4574255
Subject Item
_:vb4574255
rdf:type
n2:Context
rdf:value
The FA protein FANCD2 forms nuclear foci during S phase in the absence of exogenous DNA damage (>>9<<). Whether S phase FANCD2 foci associate with specific substructures within the nucleus is unknown.
n2:mentions
n3:12239151
Subject Item
_:vb4574256
rdf:type
n2:Context
rdf:value
Since another DNA damage response protein, NBS1, colocalizes with telomeres in non-ALT cells (>>36<<), we tested whether spontaneous FANCD2 foci colocalize with telomeres in cells which maintain telomere length by either of two different mechanisms:
n2:mentions
n3:10888888
Subject Item
_:vb4574257
rdf:type
n2:Context
rdf:value
In initial experiments, we assayed colocalization of FANCD2 foci with the telomere-binding protein TRF1 (>>37<<) (Figure 1).
n2:mentions
n3:7502076
Subject Item
_:vb4574258
rdf:type
n2:Context
rdf:value
Telomeres aggregate (cluster) in ALT cells (>>22<<,26,38). As a result, ALT cells frequently have a smaller number of TRF1 foci, which are larger than those detected in telomerase-expressing cells.
n2:mentions
n3:10913111
Subject Item
_:vb4574259
rdf:type
n2:Context
rdf:value
Telomeres aggregate (cluster) in ALT cells (22,>>26<<,38). As a result, ALT cells frequently have a smaller number of TRF1 foci, which are larger than those detected in telomerase-expressing cells.
n2:mentions
n3:10485449
Subject Item
_:vb4574260
rdf:type
n2:Context
rdf:value
Telomeres aggregate (cluster) in ALT cells (22,26,>>38<<). As a result, ALT cells frequently have a smaller number of TRF1 foci, which are larger than those detected in telomerase-expressing cells.
n2:mentions
n3:14657034
Subject Item
_:vb4574261
rdf:type
n2:Context
rdf:value
Two foci were used as the standard for colocalization, since telomeres can aggregate in ALT cells into a small number of bright telomeric foci (>>22<<,26,38). Each bar represents the average of three counts of at least 150 cells each ±SD. The levels of colocalization of FANCD2 with TRF1 in ALT cells were statistically different from those seen in telomerase-expressing cells (P < 0.01).
n2:mentions
n3:10913111
Subject Item
_:vb4574262
rdf:type
n2:Context
rdf:value
Two foci were used as the standard for colocalization, since telomeres can aggregate in ALT cells into a small number of bright telomeric foci (22,>>26<<,38). Each bar represents the average of three counts of at least 150 cells each ±SD. The levels of colocalization of FANCD2 with TRF1 in ALT cells were statistically different from those seen in telomerase-expressing cells (P < 0.01).
n2:mentions
n3:10485449
Subject Item
_:vb4574263
rdf:type
n2:Context
rdf:value
Two foci were used as the standard for colocalization, since telomeres can aggregate in ALT cells into a small number of bright telomeric foci (22,26,>>38<<). Each bar represents the average of three counts of at least 150 cells each ±SD. The levels of colocalization of FANCD2 with TRF1 in ALT cells were statistically different from those seen in telomerase-expressing cells (P < 0.01).
n2:mentions
n3:14657034
Subject Item
_:vb4574264
rdf:type
n2:Context
rdf:value
As an alternative measure of the colocalization of FANCD2 foci with telomeres in ALT cells, we labeled cells with FANCD2 antibodies and detected telomeric repeat DNA by simultaneous FISH (>>37<<,39). We found that FANCD2 foci colocalized with telomeric DNA in two different ALT cell lines, GM847 and U2OS (Figure 3A).
n2:mentions
n3:7502076
Subject Item
_:vb4574265
rdf:type
n2:Context
rdf:value
As an alternative measure of the colocalization of FANCD2 foci with telomeres in ALT cells, we labeled cells with FANCD2 antibodies and detected telomeric repeat DNA by simultaneous FISH (37,>>39<<). We found that FANCD2 foci colocalized with telomeric DNA in two different ALT cell lines, GM847 and U2OS (Figure 3A).
n2:mentions
n3:15149599
Subject Item
_:vb4574266
rdf:type
n2:Context
rdf:value
Consistent with a recent report (>>40<<), we also found that TRF1 strongly colocalized with telomeric DNA following the induction of DNA damage (data not shown).
n2:mentions
n3:17534357
Subject Item
_:vb4574267
rdf:type
n2:Context
rdf:value
The promyelocytic leukemia protein (PML) forms ALT-associated PML bodies (APBs) (>>21<<,22,26), which also contain telomeric DNA, telomere-binding proteins, and certain DNA repair proteins.
n2:mentions
n3:11082050
Subject Item
_:vb4574268
rdf:type
n2:Context
rdf:value
The promyelocytic leukemia protein (PML) forms ALT-associated PML bodies (APBs) (21,>>22<<,26), which also contain telomeric DNA, telomere-binding proteins, and certain DNA repair proteins.
n2:mentions
n3:10913111
Subject Item
_:vb4574269
rdf:type
n2:Context
rdf:value
The promyelocytic leukemia protein (PML) forms ALT-associated PML bodies (APBs) (21,22,>>26<<), which also contain telomeric DNA, telomere-binding proteins, and certain DNA repair proteins.
n2:mentions
n3:10485449
Subject Item
_:vb4574270
rdf:type
n2:Context
rdf:value
Because FANCD2 preferentially colocalizes with TRF1 at late S phase/G2 (Figure 2), and because PML also colocalizes with telomeres late in the cell cycle (21–>>23<<), we sought to determine whether FANCD2 colocalizes with PML bodies in a cell-cycle-dependent manner in ALT cells.
n2:mentions
n3:11082050 n3:15229185 n3:10913111
Subject Item
_:vb4574271
rdf:type
n2:Context
rdf:value
Since monoubiquitination is required for the assembly of FANCD2 foci in telomerase-expressing cells during S phase and in response to DNA damage (>>3<<,9), we sought to determine whether monoubiquitination is required for the colocalization of FANCD2 foci with TRF1 foci in ALT cells.
n2:mentions
n3:11239454
Subject Item
_:vb4574272
rdf:type
n2:Context
rdf:value
Since monoubiquitination is required for the assembly of FANCD2 foci in telomerase-expressing cells during S phase and in response to DNA damage (3,>>9<<), we sought to determine whether monoubiquitination is required for the colocalization of FANCD2 foci with TRF1 foci in ALT cells.
n2:mentions
n3:12239151
Subject Item
_:vb4574273
rdf:type
n2:Context
rdf:value
For this purpose, we depleted FANCA, which is a component of the FA nuclear core complex that is required for FANCD2 monoubiquitination (>>3<<,10), using a siRNA that we have described previously (10).
n2:mentions
n3:11239454
Subject Item
_:vb4574274
rdf:type
n2:Context
rdf:value
For this purpose, we depleted FANCA, which is a component of the FA nuclear core complex that is required for FANCD2 monoubiquitination (3,>>10<<), using a siRNA that we have described previously (10).
n2:mentions
n3:15314022
Subject Item
_:vb4574275
rdf:type
n2:Context
rdf:value
For this purpose, we depleted FANCA, which is a component of the FA nuclear core complex that is required for FANCD2 monoubiquitination (3,10), using a siRNA that we have described previously (>>10<<). Depletion of FANCA in ALT cells (U2OS) inhibited FANCD2 monoubiquitination, but did not deplete FANCD2, both in randomly cycling cells and following exposure to HU (Figure 5A). SiRNAs directed against FANCA also strongly inhibited
n2:mentions
n3:15314022
Subject Item
_:vb4574276
rdf:type
n2:Context
rdf:value
Thus, the assembly of FANCD2 foci is induced by DNA damage both in telomerase-expressing cells (>>10<<) and in ALT cells.
n2:mentions
n3:15314022
Subject Item
_:vb4574277
rdf:type
n2:Context
rdf:value
Importantly, FANCL is the apparent E3 ubiquitin ligase for FANCD2 (>>31<<). For this purpose, we depleted FANCL using a siRNA that has been described previously (31).
n2:mentions
n3:12973351
Subject Item
_:vb4574278
rdf:type
n2:Context
rdf:value
For this purpose, we depleted FANCL using a siRNA that has been described previously (>>31<<). Depletion of FANCL in ALT cells (U2OS) inhibited FANCD2 monoubiquitination, both in randomly cycling cells and following exposure to HU (Figure 5A). Furthermore, depletion of FANCL in U2OS ALT cells inhibited the assembly of FANCD2 foci
n2:mentions
n3:12973351
Subject Item
_:vb4574279
rdf:type
n2:Context
rdf:value
The assembly of FANCD2 foci in response to DNA damage or replication stress is regulated by the ATR checkpoint kinase in telomerase-expressing cells (>>10<<). Depletion of ATR in U2OS ALT cells using a siRNA we have described previously (10), inhibited FANCD2 monoubiquitination in HU-treated cells (Figure 6A).
n2:mentions
n3:15314022
Subject Item
_:vb4574280
rdf:type
n2:Context
rdf:value
Depletion of ATR in U2OS ALT cells using a siRNA we have described previously (>>10<<), inhibited FANCD2 monoubiquitination in HU-treated cells (Figure 6A).
n2:mentions
n3:15314022
Subject Item
_:vb4574281
rdf:type
n2:Context
rdf:value
As previously reported, however, telomere lengths were more heterogeneous in ALT cells (>>16<<,19). Thus, the longest telomeres in U2OS cells yielded signals of greater intensity, detected with Cy3-PNA, than in HeLa cells. Furthermore, while nearly all telomeres were detectable in HeLa cells, a striking number of telomeres in U2OS
n2:mentions
n3:11919561
Subject Item
_:vb4574282
rdf:type
n2:Context
rdf:value
As previously reported, however, telomere lengths were more heterogeneous in ALT cells (16,>>19<<). Thus, the longest telomeres in U2OS cells yielded signals of greater intensity, detected with Cy3-PNA, than in HeLa cells. Furthermore, while nearly all telomeres were detectable in HeLa cells, a striking number of telomeres in U2OS
n2:mentions
n3:11439347
Subject Item
_:vb4574283
rdf:type
n2:Context
rdf:value
This assay has been described previously (>>19<<,41). Depletion of FANCA or FANCD2 with the appropriate siRNA was effective in both U2OS (ALT) (Figure 5A) and HeLa (telomerase-expressing) cells (10).
n2:mentions
n3:11439347
Subject Item
_:vb4574284
rdf:type
n2:Context
rdf:value
This assay has been described previously (19,>>41<<). Depletion of FANCA or FANCD2 with the appropriate siRNA was effective in both U2OS (ALT) (Figure 5A) and HeLa (telomerase-expressing) cells (10).
n2:mentions
n3:16000404
Subject Item
_:vb4574285
rdf:type
n2:Context
rdf:value
Depletion of FANCA or FANCD2 with the appropriate siRNA was effective in both U2OS (ALT) (Figure 5A) and HeLa (telomerase-expressing) cells (>>10<<). While 17.6 ± 2.3% of the telomeres were signal-free in U2OS cells transfected with the control siRNA targeting GFP, the percentage of signal-free telomere ends was increased in U2OS cells in which either FANCD2 or FANCA was depleted
n2:mentions
n3:15314022
Subject Item
_:vb4574286
rdf:type
n2:Context
rdf:value
ALT cells maintain telomeres through homologous recombination (>>15<<,16). Homologous recombination at ALT telomeres is shown schematically in Figure 8A, and a more detailed consideration of the molecular steps that may be involved can be found elsewhere (42,43).
n2:mentions
n3:11101843
Subject Item
_:vb4574287
rdf:type
n2:Context
rdf:value
ALT cells maintain telomeres through homologous recombination (15,>>16<<). Homologous recombination at ALT telomeres is shown schematically in Figure 8A, and a more detailed consideration of the molecular steps that may be involved can be found elsewhere (42,43).
n2:mentions
n3:11919561
Subject Item
_:vb4574288
rdf:type
n2:Context
rdf:value
Homologous recombination at ALT telomeres is shown schematically in Figure 8A, and a more detailed consideration of the molecular steps that may be involved can be found elsewhere (>>42<<,43). Because depletion of FANCA or FANCD2 results in the loss of detectable telomeres in ALT cells (Figure 7), we sought to determine whether FANCA and FANCD2 are required for telomeric recombination in ALT cells. Sister chromatid
n2:mentions
n3:16756487
Subject Item
_:vb4574289
rdf:type
n2:Context
rdf:value
Homologous recombination at ALT telomeres is shown schematically in Figure 8A, and a more detailed consideration of the molecular steps that may be involved can be found elsewhere (42,>>43<<). Because depletion of FANCA or FANCD2 results in the loss of detectable telomeres in ALT cells (Figure 7), we sought to determine whether FANCA and FANCD2 are required for telomeric recombination in ALT cells. Sister chromatid exchange
n2:mentions
n3:15846103
Subject Item
_:vb4574290
rdf:type
n2:Context
rdf:value
Sister chromatid exchange at telomeres (T-SCE) can be measured by CO-FISH (>>34<<). According to the protocol that we utilized (shown schematically in Figure 8B), newly synthesized strands were degraded and only the pre-existing strands were detected by hybridization with a strand-specific telomere probe
n2:mentions
n3:15258249
Subject Item
_:vb4574291
rdf:type
n2:Context
rdf:value
Consistent with the previous reports (>>17<<,18), T-SCE was much less frequent in HeLa, which is not an ALT cell line.
n2:mentions
n3:17054727
Subject Item
_:vb4574292
rdf:type
n2:Context
rdf:value
Consistent with the previous reports (17,>>18<<), T-SCE was much less frequent in HeLa, which is not an ALT cell line.
n2:mentions
n3:15059879
Subject Item
_:vb4574293
rdf:type
n6:Section
dc:title
discussion
n6:contains
_:vb4574336 _:vb4574320 _:vb4574321 _:vb4574322 _:vb4574323 _:vb4574324 _:vb4574325 _:vb4574326 _:vb4574327 _:vb4574328 _:vb4574329 _:vb4574330 _:vb4574331 _:vb4574332 _:vb4574333 _:vb4574334 _:vb4574335 _:vb4574304 _:vb4574305 _:vb4574306 _:vb4574307 _:vb4574308 _:vb4574309 _:vb4574310 _:vb4574311 _:vb4574312 _:vb4574313 _:vb4574314 _:vb4574315 _:vb4574316 _:vb4574317 _:vb4574318 _:vb4574319 _:vb4574294 _:vb4574295 _:vb4574296 _:vb4574297 _:vb4574298 _:vb4574299 _:vb4574300 _:vb4574301 _:vb4574302 _:vb4574303
Subject Item
_:vb4574294
rdf:type
n2:Context
rdf:value
While many DNA damage response proteins localize to ALT telomeres (22–>>28<<,44–47), few, including NBS1 and SMC5/6, have been directly implicated in the maintenance of ALT telomeres (28,46).
n2:mentions
n3:12750284 n3:17589526 n3:12444098 n3:10913111 n3:10485449 n3:17959650 n3:15229185
Subject Item
_:vb4574295
rdf:type
n2:Context
rdf:value
While many DNA damage response proteins localize to ALT telomeres (22–28,44–>>47<<), few, including NBS1 and SMC5/6, have been directly implicated in the maintenance of ALT telomeres (28,46).
n2:mentions
n3:17693401 n3:15109494 n3:15075340 n3:15200954
Subject Item
_:vb4574296
rdf:type
n2:Context
rdf:value
While many DNA damage response proteins localize to ALT telomeres (22–28,44–47), few, including NBS1 and SMC5/6, have been directly implicated in the maintenance of ALT telomeres (>>28<<,46). Thus, our results, which demonstrate a role for the FA pathway, are important for understanding ALT telomere maintenance. In turn, ALT telomeres may provide an important model for analysis of the function of FA proteins in HR.
n2:mentions
n3:17589526
Subject Item
_:vb4574297
rdf:type
n2:Context
rdf:value
While many DNA damage response proteins localize to ALT telomeres (22–28,44–47), few, including NBS1 and SMC5/6, have been directly implicated in the maintenance of ALT telomeres (28,>>46<<). Thus, our results, which demonstrate a role for the FA pathway, are important for understanding ALT telomere maintenance. In turn, ALT telomeres may provide an important model for analysis of the function of FA proteins in HR.
n2:mentions
n3:17693401
Subject Item
_:vb4574298
rdf:type
n2:Context
rdf:value
We have not, however, observed co-immunoprecipitation of FANCD2 with TRF1 or TRF2, either in the chromatin fraction that contains monoubiquitinated FANCD2 (>>7<<) or under conditions of increased FANCD2 monoubiquitination following the induction of DNA damage (data not shown).
n2:mentions
n3:15454491
Subject Item
_:vb4574299
rdf:type
n2:Context
rdf:value
Our results demonstrate that the FA nuclear core complex and ATR are required both for the distribution of FANCD2 to ALT telomeres and to sites of DNA damage induced by various genotoxic agents (>>3<<,7,10). In fact, FANCD2 may localize to ALT telomeres as part of a specialized DNA damage response.
n2:mentions
n3:11239454
Subject Item
_:vb4574300
rdf:type
n2:Context
rdf:value
Our results demonstrate that the FA nuclear core complex and ATR are required both for the distribution of FANCD2 to ALT telomeres and to sites of DNA damage induced by various genotoxic agents (3,>>7<<,10). In fact, FANCD2 may localize to ALT telomeres as part of a specialized DNA damage response.
n2:mentions
n3:15454491
Subject Item
_:vb4574301
rdf:type
n2:Context
rdf:value
Our results demonstrate that the FA nuclear core complex and ATR are required both for the distribution of FANCD2 to ALT telomeres and to sites of DNA damage induced by various genotoxic agents (3,7,>>10<<). In fact, FANCD2 may localize to ALT telomeres as part of a specialized DNA damage response.
n2:mentions
n3:15314022
Subject Item
_:vb4574302
rdf:type
n2:Context
rdf:value
Furthermore, ALT cells contain telomeres with DNA termini recognized as DNA double-strand breaks (>>47<<).
n2:mentions
n3:15075340
Subject Item
_:vb4574303
rdf:type
n2:Context
rdf:value
This has been examined by a widely utilized method of FISH with a probe that recognizes TTAGGG telomeric repeats (>>41<<,48,49). Importantly, transient depletion of FANCA or FANCD2 over a period of 4 days results in a similar increase in the frequency of signal-free ends in U2OS ALT cells. Together, our results suggest that FANCA and FANCD2 may function in
n2:mentions
n3:16000404
Subject Item
_:vb4574304
rdf:type
n2:Context
rdf:value
This has been examined by a widely utilized method of FISH with a probe that recognizes TTAGGG telomeric repeats (41,>>48<<,49). Importantly, transient depletion of FANCA or FANCD2 over a period of 4 days results in a similar increase in the frequency of signal-free ends in U2OS ALT cells. Together, our results suggest that FANCA and FANCD2 may function in a
n2:mentions
n3:16264192
Subject Item
_:vb4574305
rdf:type
n2:Context
rdf:value
This has been examined by a widely utilized method of FISH with a probe that recognizes TTAGGG telomeric repeats (41,48,>>49<<). Importantly, transient depletion of FANCA or FANCD2 over a period of 4 days results in a similar increase in the frequency of signal-free ends in U2OS ALT cells. Together, our results suggest that FANCA and FANCD2 may function in a
n2:mentions
n3:15079066
Subject Item
_:vb4574306
rdf:type
n2:Context
rdf:value
In addition to gradual telomere attrition, ALT cells display rapid decreases or increases of telomere length of multiple kilobases (>>50<<). We propose that a deficiency for FANCD2 or its monoubiquitination may lead to rapid telomere shortening in ALT cells due, at least in part, to a demonstrated defect in the T-SCE that is required for telomere lengthening.
n2:mentions
n3:7957062
Subject Item
_:vb4574307
rdf:type
n2:Context
rdf:value
Monoubiquitinated FANCD2 might also normally act to stabilize or cap linear DNA present at APBs (>>51<<). In this context, it is interesting that the telomeric protein, POT1b, is involved both in stabilizing telomeres and in regulating T-SCE (52).
n2:mentions
n3:17652140
Subject Item
_:vb4574308
rdf:type
n2:Context
rdf:value
In this context, it is interesting that the telomeric protein, POT1b, is involved both in stabilizing telomeres and in regulating T-SCE (>>52<<).
n2:mentions
n3:17053789
Subject Item
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While lymphoblasts from FA patients have shorter telomeres relative to age-matched controls (53–>>55<<), a previous study using mouse and human cells deficient for FA nuclear core complex proteins demonstrated no direct role for the FA pathway in telomere maintenance in non-ALT cells (56).
n2:mentions
n3:11591364 n3:11854176 n3:10554797
Subject Item
_:vb4574310
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telomeres relative to age-matched controls (53–55), a previous study using mouse and human cells deficient for FA nuclear core complex proteins demonstrated no direct role for the FA pathway in telomere maintenance in non-ALT cells (>>56<<). This is in accord with our finding that FANCD2 does not colocalize with telomeres in non-ALT cells and therefore is not expected to have a role in telomere maintenance in such cells.
n2:mentions
n3:15319283
Subject Item
_:vb4574311
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We demonstrate that deficiency for FANCA or FANCD2 results in a decrease in T-SCE, which is a form of homologous recombination required for ALT telomere maintenance (>>15<<,16). It should be noted that not all proteins that have an integral role in homologous recombination are required for T-SCE or for ALT telomere maintenance.
n2:mentions
n3:11101843
Subject Item
_:vb4574312
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We demonstrate that deficiency for FANCA or FANCD2 results in a decrease in T-SCE, which is a form of homologous recombination required for ALT telomere maintenance (15,>>16<<). It should be noted that not all proteins that have an integral role in homologous recombination are required for T-SCE or for ALT telomere maintenance.
n2:mentions
n3:11919561
Subject Item
_:vb4574313
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An example of this is RAD54 (>>17<<). Thus, FA proteins may be involved in a specific form of HR that is utilized to maintain ALT telomeres.
n2:mentions
n3:17054727
Subject Item
_:vb4574314
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Deficiency for FA proteins, such as FANCA, FANCG and FANCD2, is associated with a modest defect in DNA double-strand break-induced HR (57–>>59<<). Based upon such results, it has been suggested that FA proteins, other than BRCA2/FANCD1 and its partner, PALB2/FANCN, have a regulatory role in HR, rather than a direct mechanistic function in this type of repair (60).
n2:mentions
n3:15650050 n3:15905196 n3:12861027
Subject Item
_:vb4574315
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Based upon such results, it has been suggested that FA proteins, other than BRCA2/FANCD1 and its partner, PALB2/FANCN, have a regulatory role in HR, rather than a direct mechanistic function in this type of repair (>>60<<). The assays of DNA double-strand break-induced HR described earlier utilized a reporter introduced into DNA (57–59). In contrast, the function of FA proteins in T-SCE represents homologous recombination in a physiological context. As
n2:mentions
n3:16859679
Subject Item
_:vb4574316
rdf:type
n2:Context
rdf:value
The assays of DNA double-strand break-induced HR described earlier utilized a reporter introduced into DNA (57–>>59<<). In contrast, the function of FA proteins in T-SCE represents homologous recombination in a physiological context. As such, ALT telomeres may represent an important system for understanding the function of FA proteins in DNA repair.
n2:mentions
n3:15650050 n3:15905196 n3:12861027
Subject Item
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Incorporation of bromodeoxyuridine at APBs during late S phase/G2 (21–>>23<<) could be related either to replication of telomeric DNA or homologous recombination at telomeres.
n2:mentions
n3:11082050 n3:15229185 n3:10913111
Subject Item
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Second, FA proteins have been implicated in DNA repair in non-ALT cells (57–>>59<<), and FANCD2 is not a constitutive component of the replication machinery (61).
n2:mentions
n3:15650050 n3:15905196 n3:12861027
Subject Item
_:vb4574319
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Second, FA proteins have been implicated in DNA repair in non-ALT cells (57–59), and FANCD2 is not a constitutive component of the replication machinery (>>61<<). Third, neither FANCD2 nor its monoubiquitination significantly influences the rate of bulk DNA replication (9). Finally, similar to FANCD2, other DNA repair-related proteins, such as NBS1 and SMC5/6, have a role in T-SCE and colocalize
n2:mentions
n3:15115758
Subject Item
_:vb4574320
rdf:type
n2:Context
rdf:value
Third, neither FANCD2 nor its monoubiquitination significantly influences the rate of bulk DNA replication (>>9<<). Finally, similar to FANCD2, other DNA repair-related proteins, such as NBS1 and SMC5/6, have a role in T-SCE and colocalize with APBs during late S phase/G2 (22,28).
n2:mentions
n3:12239151
Subject Item
_:vb4574321
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n2:Context
rdf:value
Finally, similar to FANCD2, other DNA repair-related proteins, such as NBS1 and SMC5/6, have a role in T-SCE and colocalize with APBs during late S phase/G2 (>>22<<,28).
n2:mentions
n3:10913111
Subject Item
_:vb4574322
rdf:type
n2:Context
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Finally, similar to FANCD2, other DNA repair-related proteins, such as NBS1 and SMC5/6, have a role in T-SCE and colocalize with APBs during late S phase/G2 (22,>>28<<).
n2:mentions
n3:17589526
Subject Item
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The DNA repair proteins WRN and Ku70, and the telomeric proteins Pot1 a and b, suppress sister chromatid exchange at telomeres (T-SCE) (>>48<<,52,62,63).
n2:mentions
n3:16264192
Subject Item
_:vb4574324
rdf:type
n2:Context
rdf:value
The DNA repair proteins WRN and Ku70, and the telomeric proteins Pot1 a and b, suppress sister chromatid exchange at telomeres (T-SCE) (48,>>52<<,62,63). In contrast, the FA pathway, along with SMC5/6 (28), appears to be required for the T-SCE that drives telomere maintenance in ALT cells (15,16). The functional relationship of SMC5/6 to FA proteins in T-SCE, if any, is unknown at
n2:mentions
n3:17053789
Subject Item
_:vb4574325
rdf:type
n2:Context
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The DNA repair proteins WRN and Ku70, and the telomeric proteins Pot1 a and b, suppress sister chromatid exchange at telomeres (T-SCE) (48,52,>>62<<,63). In contrast, the FA pathway, along with SMC5/6 (28), appears to be required for the T-SCE that drives telomere maintenance in ALT cells (15,16). The functional relationship of SMC5/6 to FA proteins in T-SCE, if any, is unknown at
n2:mentions
n3:16845382
Subject Item
_:vb4574326
rdf:type
n2:Context
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The DNA repair proteins WRN and Ku70, and the telomeric proteins Pot1 a and b, suppress sister chromatid exchange at telomeres (T-SCE) (48,52,62,>>63<<). In contrast, the FA pathway, along with SMC5/6 (28), appears to be required for the T-SCE that drives telomere maintenance in ALT cells (15,16). The functional relationship of SMC5/6 to FA proteins in T-SCE, if any, is unknown at
n2:mentions
n3:16839876
Subject Item
_:vb4574327
rdf:type
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In contrast, the FA pathway, along with SMC5/6 (>>28<<), appears to be required for the T-SCE that drives telomere maintenance in ALT cells (15,16).
n2:mentions
n3:17589526
Subject Item
_:vb4574328
rdf:type
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In contrast, the FA pathway, along with SMC5/6 (28), appears to be required for the T-SCE that drives telomere maintenance in ALT cells (>>15<<,16). The functional relationship of SMC5/6 to FA proteins in T-SCE, if any, is unknown at present.
n2:mentions
n3:11101843
Subject Item
_:vb4574329
rdf:type
n2:Context
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In contrast, the FA pathway, along with SMC5/6 (28), appears to be required for the T-SCE that drives telomere maintenance in ALT cells (15,>>16<<). The functional relationship of SMC5/6 to FA proteins in T-SCE, if any, is unknown at present.
n2:mentions
n3:11919561
Subject Item
_:vb4574330
rdf:type
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Further, SMC5/6 are required for the formation of APBs and for T-SCE in ALT cells (>>28<<). Our findings suggest that monoubiquitination of FANCD2 is also required for colocalization of this protein with APBs and for T-SCE in ALT cells.
n2:mentions
n3:17589526
Subject Item
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Indeed, the most prevalent malignancies in FA patients are AML and squamous carcinoma of the head and neck (>>1<<). These cancers utilize ALT with a low frequency (14,64).
n2:mentions
n3:12518367
Subject Item
_:vb4574332
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Indeed, the most prevalent malignancies in FA patients are AML and squamous carcinoma of the head and neck (1). These cancers utilize ALT with a low frequency (>>14<<,64).
n2:mentions
n3:11850785
Subject Item
_:vb4574333
rdf:type
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Indeed, the most prevalent malignancies in FA patients are AML and squamous carcinoma of the head and neck (1). These cancers utilize ALT with a low frequency (14,>>64<<).
n2:mentions
n3:15671549
Subject Item
_:vb4574334
rdf:type
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Because of a defect in the cellular response to DNA damage, FA patients are potentially hypersensitive to radiotherapy or chemotherapy (>>1<<,65). If tumors in FA patients uniquely develop through reactivation of telomerase, perhaps inhibition of telomerase (66) will be a more effective therapeutic strategy to which FA patients are not hypersensitive.
n2:mentions
n3:12518367
Subject Item
_:vb4574335
rdf:type
n2:Context
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Because of a defect in the cellular response to DNA damage, FA patients are potentially hypersensitive to radiotherapy or chemotherapy (1,>>65<<). If tumors in FA patients uniquely develop through reactivation of telomerase, perhaps inhibition of telomerase (66) will be a more effective therapeutic strategy to which FA patients are not hypersensitive.
n2:mentions
n3:12175566
Subject Item
_:vb4574336
rdf:type
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If tumors in FA patients uniquely develop through reactivation of telomerase, perhaps inhibition of telomerase (>>66<<) will be a more effective therapeutic strategy to which FA patients are not hypersensitive.
n2:mentions
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7
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7
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5
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5
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5
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5
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5
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5
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4
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4
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4
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4
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4
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4
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4
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4
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4
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4
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4
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4
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4
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4
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4
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4
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4
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3
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3
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3
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3
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3
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3
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3
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3
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3
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3
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3
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3
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3
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3
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3
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3
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3
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