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n3:pmcid: PMC0
bibo:doi: 10.7554%2FeLife.02443.024
n6:contains: _:vb34204991 _:vb34205011 _:vb34205022 _:vb34205058

Subject Item: _:vb34204991
rdf:type: n6:Section
dc:title: introduction
n6:contains: _:vb34205008 _:vb34205009 _:vb34205010 _:vb34205000 _:vb34205001 _:vb34205002 _:vb34205003 _:vb34205004 _:vb34205005 _:vb34205006 _:vb34205007 _:vb34204992 _:vb34204993 _:vb34204994 _:vb34204995 _:vb34204996 _:vb34204997 _:vb34204998 _:vb34204999

Subject Item: _:vb34204992
rdf:type: n3:Context
rdf:value: During this process, pre-existing or so-called parental histones are recycled and assembled into nucleosomes together with de novo synthesized histones (Alabert and Groth, 2012; Annunziato, >>2012<<). To compensate for the high demand of histone proteins during DNA replication, the canonical histones H1, H2A, H2B, H3, and H4, which are encoded by multiple gene copies in higher eukaryotes, are highly and exclusively expressed in S
n3:mentions: n2:24459722

Subject Item: _:vb34204993
rdf:type: n3:Context
rdf:value: The assembly of chromatin is mediated by an interplay of components of the DNA replication machinery and histone chaperones, which mediate the deposition of histones into nucleosomes (Alabert and Groth, 2012; Annunziato, >>2012<<). Apparently, the pace of DNA synthesis is tightly coupled to the assembly of newly synthesized DNA into chromatin.
n3:mentions: n2:24459722

Subject Item: _:vb34204994
rdf:type: n3:Context
rdf:value: Multiple studies showed that the depletion of the histone chaperones Asf1 and CAF-1 results in a slow down of DNA synthesis during S phase (Hoek and Stillman, 2003; Ye et al., >>2003<<; Nabatiyan and Krude, 2004; Groth et al., 2007; Takami et al., 2007) preceding the accumulation of DNA damage in mammalian cells (Hoek and Stillman, 2003; Ye et al., 2003).
n3:mentions: n2:12620223

Subject Item: _:vb34204995
rdf:type: n3:Context
rdf:value: Multiple studies showed that the depletion of the histone chaperones Asf1 and CAF-1 results in a slow down of DNA synthesis during S phase (Hoek and Stillman, 2003; Ye et al., 2003; Nabatiyan and Krude, >>2004<<; Groth et al., 2007; Takami et al., 2007) preceding the accumulation of DNA damage in mammalian cells (Hoek and Stillman, 2003; Ye et al., 2003).
n3:mentions: n2:15024074

Subject Item: _:vb34204996
rdf:type: n3:Context
rdf:value: Multiple studies showed that the depletion of the histone chaperones Asf1 and CAF-1 results in a slow down of DNA synthesis during S phase (Hoek and Stillman, 2003; Ye et al., 2003; Nabatiyan and Krude, 2004; Groth et al., >>2007<<; Takami et al., 2007) preceding the accumulation of DNA damage in mammalian cells (Hoek and Stillman, 2003; Ye et al., 2003).
n3:mentions: n2:18096807

Subject Item: _:vb34204997
rdf:type: n3:Context
rdf:value: studies showed that the depletion of the histone chaperones Asf1 and CAF-1 results in a slow down of DNA synthesis during S phase (Hoek and Stillman, 2003; Ye et al., 2003; Nabatiyan and Krude, 2004; Groth et al., 2007; Takami et al., >>2007<<) preceding the accumulation of DNA damage in mammalian cells (Hoek and Stillman, 2003; Ye et al., 2003).
n3:mentions: n2:17065558

Subject Item: _:vb34204998
rdf:type: n3:Context
rdf:value: synthesis during S phase (Hoek and Stillman, 2003; Ye et al., 2003; Nabatiyan and Krude, 2004; Groth et al., 2007; Takami et al., 2007) preceding the accumulation of DNA damage in mammalian cells (Hoek and Stillman, 2003; Ye et al., >>2003<<). Also, diminishing histone supply during S phase through knock down of SLBP, which is required for histone mRNA stability and translation, decreases the rate of DNA synthesis (Zhao et al., 2004).
n3:mentions: n2:12620223

Subject Item: _:vb34204999
rdf:type: n3:Context
rdf:value: Also, diminishing histone supply during S phase through knock down of SLBP, which is required for histone mRNA stability and translation, decreases the rate of DNA synthesis (Zhao et al., >>2004<<). A recent study that targeted SLBP together with FLASH, a factor that is required for histone mRNA transcription and processing (Barcaroli et al., 2006; Yang et al., 2009), revealed that replication fork progression depends on nucleosome
n3:mentions: n2:15546920

Subject Item: _:vb34205000
rdf:type: n3:Context
rdf:value: A recent study that targeted SLBP together with FLASH, a factor that is required for histone mRNA transcription and processing (Barcaroli et al., 2006; Yang et al., >>2009<<), revealed that replication fork progression depends on nucleosome assembly potentially through a mechanism based on a feedback from the histone chaperone CAF-1 to the replicative helicase and/or the unloading of PCNA from newly
n3:mentions: n2:19854135

Subject Item: _:vb34205001
rdf:type: n3:Context
rdf:value: on nucleosome assembly potentially through a mechanism based on a feedback from the histone chaperone CAF-1 to the replicative helicase and/or the unloading of PCNA from newly synthesized DNA upon nucleosome assembly (Groth et al., >>2007<<; Mejlvang et al., 2014).
n3:mentions: n2:18096807

Subject Item: _:vb34205002
rdf:type: n3:Context
rdf:value: potentially through a mechanism based on a feedback from the histone chaperone CAF-1 to the replicative helicase and/or the unloading of PCNA from newly synthesized DNA upon nucleosome assembly (Groth et al., 2007; Mejlvang et al., >>2014<<).
n3:mentions: n2:24379417

Subject Item: _:vb34205003
rdf:type: n3:Context
rdf:value: The coupling of replication fork progression and nucleosome assembly might compensate for short-term fluctuations in histone availability (Mejlvang et al., >>2014<<). However, it is still unclear whether chromatin integrity is monitored after or during DNA replication.
n3:mentions: n2:24379417

Subject Item: _:vb34205004
rdf:type: n3:Context
rdf:value: Genome integrity during S phase is governed by the ATR/Chk1 and ATM/Chk2 checkpoint mechanisms that sense replication stress and DNA damage, respectively (Bartek and Lukas, >>2007<<; Cimprich and Cortez, 2008).
n3:mentions: n2:17303408

Subject Item: _:vb34205005
rdf:type: n3:Context
rdf:value: Lack of CAF-1 or Asf1 function leads to accumulation of DNA damage and activation of the ATM/Chk2 pathway (Hoek and Stillman, 2003; Ye et al., >>2003<<). These findings led to the hypothesis that chromatin assembly is monitored indirectly through accumulation of DNA lesions in response to stalled replication forks. However, since these chaperones have multiple functions such as unwinding
n3:mentions: n2:12620223

Subject Item: _:vb34205006
rdf:type: n3:Context
rdf:value: However, since these chaperones have multiple functions such as unwinding of DNA during replication, in DNA repair (Gaillard et al., >>1996<<; Green and Almouzni, 2003; Schöpf et al., 2012) as well as other nuclear processes (Quivy et al., 2004; Houlard et al., 2006).
n3:mentions: n2:8808624

Subject Item: _:vb34205007
rdf:type: n3:Context
rdf:value: However, since these chaperones have multiple functions such as unwinding of DNA during replication, in DNA repair (Gaillard et al., 1996; Green and Almouzni, >>2003<<; Schöpf et al., 2012) as well as other nuclear processes (Quivy et al., 2004; Houlard et al., 2006).
n3:mentions: n2:14517254

Subject Item: _:vb34205008
rdf:type: n3:Context
rdf:value: since these chaperones have multiple functions such as unwinding of DNA during replication, in DNA repair (Gaillard et al., 1996; Green and Almouzni, 2003; Schöpf et al., 2012) as well as other nuclear processes (Quivy et al., >>2004<<; Houlard et al., 2006). These multiple functions of these chaperones make it difficult to assess the direct effects of defective chromatin assembly.
n3:mentions: n2:15306854

Subject Item: _:vb34205009
rdf:type: n3:Context
rdf:value: have multiple functions such as unwinding of DNA during replication, in DNA repair (Gaillard et al., 1996; Green and Almouzni, 2003; Schöpf et al., 2012) as well as other nuclear processes (Quivy et al., 2004; Houlard et al., >>2006<<). These multiple functions of these chaperones make it difficult to assess the direct effects of defective chromatin assembly.
n3:mentions: n2:17083276

Subject Item: _:vb34205010
rdf:type: n3:Context
rdf:value: Taking advantage of a histone null mutation in a higher eukaryote that recently became available in Drosophila melanogaster (Günesdogan et al., >>2010<<), we directly addressed the requirement of canonical histone supply for DNA replication and cell cycle progression in a developing organism.
n3:mentions: n2:20814422

Subject Item: _:vb34205011
rdf:type: n6:Section
dc:title: materials and methods
n6:contains: _:vb34205016 _:vb34205017 _:vb34205018 _:vb34205019 _:vb34205020 _:vb34205021 _:vb34205012 _:vb34205013 _:vb34205014 _:vb34205015

Subject Item: _:vb34205012
rdf:type: n3:Context
rdf:value: Construction of Df(2L)HisC and histone transgenes was described previously (Günesdogan et al., >>2010<<). The lokP6 Df(2L)HisC double mutant was constructed from lokP6 (Abdu et al., 2002) by meiotic recombination.
n3:mentions: n2:20814422

Subject Item: _:vb34205013
rdf:type: n3:Context
rdf:value: The lokP6 Df(2L)HisC double mutant was constructed from lokP6 (Abdu et al., >>2002<<) by meiotic recombination.
n3:mentions: n2:12361566

Subject Item: _:vb34205014
rdf:type: n3:Context
rdf:value: 2xHis-GU flies were homozygous for the M{1xHisGU.wt}ZH-86Fb transgene (Günesdogan et al., >>2010<<). M{1xHisGU.
n3:mentions: n2:20814422

Subject Item: _:vb34205015
rdf:type: n3:Context
rdf:value: Fixation, antibody staining, BrdU incorporation, and RNA in situ hybridisation procedures were described previously (Günesdogan et al., >>2010<<). Different from our standard protocol, we reduced the fixation time to 5 min and used 37% PFA instead of 4% PFA to fix embryos after UVC treatment. For experiments that required visualization of the tubulin cytoskeleton, we fixed as
n3:mentions: n2:20814422

Subject Item: _:vb34205016
rdf:type: n3:Context
rdf:value: For experiments that required visualization of the tubulin cytoskeleton, we fixed as described (Karr and Alberts, >>1986<<). Tissue culture cells were grown in µ-slide eight-well ibidi dishes (IBIDI, Martinsried, Germany) and fixed and treated in these wells by the same procedures as embryos (Günesdogan et al., 2010). Primary antibodies used here were: rabbit
n3:mentions: n2:3514634

Subject Item: _:vb34205017
rdf:type: n3:Context
rdf:value: Tissue culture cells were grown in µ-slide eight-well ibidi dishes (IBIDI, Martinsried, Germany) and fixed and treated in these wells by the same procedures as embryos (Günesdogan et al., >>2010<<). Primary antibodies used here were: rabbit anti-Cyclin B (Jacobs et al., 1998) (1: 3000), chicken anti-β-Galactosidase (1:1000; Abcam, Cambridge, UK), H2Av pS137 (γH2Av; 1:500; Rockland, Gilbertsville, PA), rabbit anti-Chk1 phospho-S345
n3:mentions: n2:20814422

Subject Item: _:vb34205018
rdf:type: n3:Context
rdf:value: Primary antibodies used here were: rabbit anti-Cyclin B (Jacobs et al., >>1998<<) (1: 3000), chicken anti-β-Galactosidase (1:1000; Abcam, Cambridge, UK), H2Av pS137 (γH2Av; 1:500; Rockland, Gilbertsville, PA), rabbit anti-Chk1 phospho-S345 (1:300; Abcam), mouse anti-α Tubulin DM1A (1:500; Sigma-Aldrich, Taufkirchen,
n3:mentions: n2:9851980

Subject Item: _:vb34205019
rdf:type: n3:Context
rdf:value: Antisense string RNA was obtained by in vitro transcription and detected as described previously (Günesdogan et al., >>2010<<) using biotinylated secondary antibodies.
n3:mentions: n2:20814422

Subject Item: _:vb34205020
rdf:type: n3:Context
rdf:value: UV irradiation (254 nm) was done at 200 mJ/cm2 as described (Zhou and Steller, >>2003<<), and embryos were aged 45 min before fixation.
n3:mentions: n2:12689597

Subject Item: _:vb34205021
rdf:type: n3:Context
rdf:value: For inhibitor treatment, we used the same procedure as for BrdU incorporation (Günesdogan et al., >>2010<<), replacing the BrdU with 10 µM VE-821 (Selleckchem, Houston, TX) or 10 µM CHIR-124 (Selleckchem) and incubation of 45 min at RT before fixation.
n3:mentions: n2:20814422

Subject Item: _:vb34205022
rdf:type: n6:Section
dc:title: results
n6:contains: _:vb34205056 _:vb34205057 _:vb34205023 _:vb34205052 _:vb34205053 _:vb34205054 _:vb34205055 _:vb34205048 _:vb34205049 _:vb34205050 _:vb34205051 _:vb34205044 _:vb34205045 _:vb34205046 _:vb34205047 _:vb34205040 _:vb34205041 _:vb34205042 _:vb34205043 _:vb34205036 _:vb34205037 _:vb34205038 _:vb34205039 _:vb34205032 _:vb34205033 _:vb34205034 _:vb34205035 _:vb34205028 _:vb34205029 _:vb34205030 _:vb34205031 _:vb34205024 _:vb34205025 _:vb34205026 _:vb34205027

Subject Item: _:vb34205023
rdf:type: n3:Context
rdf:value: The histone null mutation in D. melanogaster, called Df(2L)HisC, lacks all genes encoding the canonical histones (Günesdogan et al., >>2010<<). Df(2L)HisC homozygous mutant animals (hereafter referred to as HisC mutants) that are derived from heterozygous parents contain only maternal histone mRNA and proteins, which are sufficient to complete the first 14 cell division cycles
n3:mentions: n2:20814422

Subject Item: _:vb34205024
rdf:type: n3:Context
rdf:value: (hereafter referred to as HisC mutants) that are derived from heterozygous parents contain only maternal histone mRNA and proteins, which are sufficient to complete the first 14 cell division cycles of the embryo (Günesdogan et al., >>2010<<). HisC mutant embryos arrest before the onset of mitosis in cycle 15 (M15) (Günesdogan et al., 2010).
n3:mentions: n2:20814422

Subject Item: _:vb34205025
rdf:type: n3:Context
rdf:value: HisC mutant embryos arrest before the onset of mitosis in cycle 15 (M15) (Günesdogan et al., >>2010<<). This highly uniform phenotype is likely due to the degradation of maternal histone mRNAs during the first G2 phase of embryogenesis in cell cycle 14 (Marzluff et al., 2008; O'Farrell et al., 1989) combined with the complete lack of
n3:mentions: n2:20814422

Subject Item: _:vb34205026
rdf:type: n3:Context
rdf:value: This highly uniform phenotype is likely due to the degradation of maternal histone mRNAs during the first G2 phase of embryogenesis in cell cycle 14 (Marzluff et al., 2008; O'Farrell et al., >>1989<<) combined with the complete lack of zygotic histone gene expression during S phase of cell cycle 15 (S15) (Günesdogan et al., 2010).
n3:mentions: n2:2683080

Subject Item: _:vb34205027
rdf:type: n3:Context
rdf:value: during the first G2 phase of embryogenesis in cell cycle 14 (Marzluff et al., 2008; O'Farrell et al., 1989) combined with the complete lack of zygotic histone gene expression during S phase of cell cycle 15 (S15) (Günesdogan et al., >>2010<<). In order to verify that the lack of histone transcription also results in a diminished pool of histone proteins in S15, we compared the protein levels of histone H2B and H3 of wild type embryos that are in S15 at 4–5 hr after egg laying
n3:mentions: n2:20814422

Subject Item: _:vb34205028
rdf:type: n3:Context
rdf:value: in S15, we compared the protein levels of histone H2B and H3 of wild type embryos that are in S15 at 4–5 hr after egg laying (AEL) to sorted HisC mutant embryos that are still in S15 at 5.5–6.5 hr AEL (see below and Günesdogan et al., >>2010<<) by quantitative Western blotting (Figure 1A,B).
n3:mentions: n2:20814422

Subject Item: _:vb34205029
rdf:type: n3:Context
rdf:value: Arrested HisC mutant cells express high levels of mitotic Cyclin B suggesting a cell cycle arrest in G2 phase of cycle 15 (G215) before mitosis (Günesdogan et al., >>2010<<; Lehner and O'Farrell, 1990; Figure 2A). Consistent with this, we did not observe degradation of the mitotic Cyclin A or assembly of mitotic spindles in HisC mutant cells (Figure 2—figure supplement 1).
n3:mentions: n2:20814422

Subject Item: _:vb34205030
rdf:type: n3:Context
rdf:value: Arrested HisC mutant cells express high levels of mitotic Cyclin B suggesting a cell cycle arrest in G2 phase of cycle 15 (G215) before mitosis (Günesdogan et al., 2010; Lehner and O'Farrell, >>1990<<; Figure 2A). Consistent with this, we did not observe degradation of the mitotic Cyclin A or assembly of mitotic spindles in HisC mutant cells (Figure 2—figure supplement 1).
n3:mentions: n2:2139805

Subject Item: _:vb34205031
rdf:type: n3:Context
rdf:value: a uniform pattern and dorsal cells a punctuate pattern of BrdU incorporation (Figure 2G,H), which is characteristic for the replication of euchromatin and heterochromatin in early and late S phase, respectively (Shermoen et al., >>2010<<). Although we cannot exclude that the lack of histone synthesis in HisC mutants interfered with firing of individual origins, the results suggest that both early and late replication origins are activated in HisC mutants.
n3:mentions: n2:21074439

Subject Item: _:vb34205032
rdf:type: n3:Context
rdf:value: of histones in cultured cells leads to a slow down of replication fork movement and it was proposed that this mechanism might avoid chromatin assembly defects due to short-term fluctuations in histone availability (Mejlvang et al., >>2014<<). Thus, we asked whether S phase could be faithfully completed under diminished but constant histone supply and whether there is a direct dose dependent relation between histone synthesis and the length of S phase.
n3:mentions: n2:24379417

Subject Item: _:vb34205033
rdf:type: n3:Context
rdf:value: In contrast, embryos containing 12xHis-GUs were fully rescued and entered M15 at the same time as the wild type cells, that is, 4.5–5 hr AEL as shown previously (Günesdogan et al., >>2010<<). These results establish that the length of S phase directly correlates with the transgene-derived de novo histone supply. In addition, our data indicate that the mechanisms adjusting replication fork movement to the available histone
n3:mentions: n2:20814422

Subject Item: _:vb34205034
rdf:type: n3:Context
rdf:value: We previously described experiments showing the stereotyped cell cycle progression in wild type embryos (Günesdogan et al., >>2010<<). AEL: after egg laying, scale bars: 100 µm in columns 1–2, 10 µm in columns 3–5. 3.5–4 hr AEL: (A) dorsal epidermal cells degraded Cyclin B, completed M14 and entered S15 as shown by the incorporation of BrdU (arrowheads). (B) Ventral
n3:mentions: n2:20814422

Subject Item: _:vb34205035
rdf:type: n3:Context
rdf:value: Wild type embryos at this developmental stage stop to proliferate after M16 by entering a G1/0 phase (Knoblich et al., >>1994<<). 2xHis-GU embryos apparently also enter a G1/0 phase, enforced by the ongoing developmental program.
n3:mentions: n2:8156587

Subject Item: _:vb34205036
rdf:type: n3:Context
rdf:value: We previously described experiments showing the stereotyped cell cycle progression in wild type embryos (Günesdogan et al., >>2010<<). AEL: after egg laying, scale bars: 100 µm in columns 1–2, 10 µm in columns 3–5. 3.5–4 hr AEL: (A) dorsal epidermal cells degraded Cyclin B, completed M14, and entered S15 as shown by the incorporation of BrdU (arrowheads). (B) Ventral
n3:mentions: n2:20814422

Subject Item: _:vb34205037
rdf:type: n3:Context
rdf:value: During and after germ band retraction (K and L), most cells did not reaccumulate Cyclin B or incorporated BrdU, suggesting that they stopped proliferating, which is similar to wild type at this developmental stage (Günesdogan et al., >>2010<<).
n3:mentions: n2:20814422

Subject Item: _:vb34205038
rdf:type: n3:Context
rdf:value: Several studies showed that mammalian tissue culture cells depleted for CAF-1 accumulate in S phase due to a decreased rate of DNA replication (Hoek and Stillman, 2003; Ye et al., >>2003<<; Nabatiyan and Krude, 2004; Takami et al., 2007) followed by accumulation of DNA damage and activation of the conventional DNA damage checkpoints (Hoek and Stillman, 2003; Ye et al., 2003).
n3:mentions: n2:12620223

Subject Item: _:vb34205039
rdf:type: n3:Context
rdf:value: Several studies showed that mammalian tissue culture cells depleted for CAF-1 accumulate in S phase due to a decreased rate of DNA replication (Hoek and Stillman, 2003; Ye et al., 2003; Nabatiyan and Krude, >>2004<<; Takami et al., 2007) followed by accumulation of DNA damage and activation of the conventional DNA damage checkpoints (Hoek and Stillman, 2003; Ye et al., 2003).
n3:mentions: n2:15024074

Subject Item: _:vb34205040
rdf:type: n3:Context
rdf:value: Several studies showed that mammalian tissue culture cells depleted for CAF-1 accumulate in S phase due to a decreased rate of DNA replication (Hoek and Stillman, 2003; Ye et al., 2003; Nabatiyan and Krude, 2004; Takami et al., >>2007<<) followed by accumulation of DNA damage and activation of the conventional DNA damage checkpoints (Hoek and Stillman, 2003; Ye et al., 2003).
n3:mentions: n2:17065558

Subject Item: _:vb34205041
rdf:type: n3:Context
rdf:value: (Hoek and Stillman, 2003; Ye et al., 2003; Nabatiyan and Krude, 2004; Takami et al., 2007) followed by accumulation of DNA damage and activation of the conventional DNA damage checkpoints (Hoek and Stillman, 2003; Ye et al., >>2003<<). However, it remained unclear whether this S phase arrest represents a direct consequence of a failure in chromatin assembly as yeast cells, for example, can complete one round of replication after the depletion of histone H4 (Kim et al.
n3:mentions: n2:12620223

Subject Item: _:vb34205042
rdf:type: n3:Context
rdf:value: it remained unclear whether this S phase arrest represents a direct consequence of a failure in chromatin assembly as yeast cells, for example, can complete one round of replication after the depletion of histone H4 (Kim et al., >>1988<<). In order to address whether DNA replication can be completed in the absence of de novo histone synthesis, we quantified the amount of nuclear DNA in DAPI-stained HisC mutant cells and compared it with wild type control cells during
n3:mentions: n2:3046933

Subject Item: _:vb34205043
rdf:type: n3:Context
rdf:value: HisC mutant cells accumulate DNA damage and activate the DNA damage checkpoints, we stained for the phosphorylated histone variant H2Av (γH2Av), which is like its vertebrate ortholog γH2AX a marker of DNA damage (Madigan et al., >>2002<<). We found that γH2Av can be induced by ionizing irradiation that causes double strand breaks (DSBs) both in wild type and HisC mutant embryos, showing that the ATM/Chk2 checkpoint mechanism is still functional in HisC mutant cells
n3:mentions: n2:12202754

Subject Item: _:vb34205044
rdf:type: n3:Context
rdf:value: Finally, we performed genetic tests using mutants of loki (lok), the Drosophila DNA damage checkpoint kinase chk2 (Xu et al., >>2001<<). Homozygous lok mutants are viable and fertile. In contrast, lok, HisC double mutant embryos exhibited the HisC phenotype (Figure 4F–H). Hence, the cell cycle arrest in HisC mutant embryos is not mediated by the chk2-dependent DNA damage
n3:mentions: n2:11728459

Subject Item: _:vb34205045
rdf:type: n3:Context
rdf:value: Mutations in the Drosophila ortholog of Chk1 (GRP) show developmental defects prior to cell cycle 15, excluding genetic experiments as we performed for lok (Fogarty et al., >>1994<<; Su et al., 1999).
n3:mentions: n2:7925016

Subject Item: _:vb34205046
rdf:type: n3:Context
rdf:value: Mutations in the Drosophila ortholog of Chk1 (GRP) show developmental defects prior to cell cycle 15, excluding genetic experiments as we performed for lok (Fogarty et al., 1994; Su et al., >>1999<<). Thus, we tested ATR/Chk1 checkpoint activation by using a phosphospecific antibody that recognizes the ATR-dependent phosphorylation of S345 in human Chk1 in response to replicative stress, for example, UV irradiation or HU treatment
n3:mentions: n2:10469601

Subject Item: _:vb34205047
rdf:type: n3:Context
rdf:value: checkpoint activation by using a phosphospecific antibody that recognizes the ATR-dependent phosphorylation of S345 in human Chk1 in response to replicative stress, for example, UV irradiation or HU treatment (Zhao and Piwnica-Worms, >>2001<<). This antibody is expected to cross-react with Drosophila GRP due to sequence similarity and detected a single band in Western blots (Figure 5—figure supplement 1) as well as a clear signal in immunofluorescence (Figure 5—figure
n3:mentions: n2:11390642

Subject Item: _:vb34205048
rdf:type: n3:Context
rdf:value: To test whether the ATR/Chk1 checkpoint is functional in HisC mutant embryos, we irradiated embryos with UV light (254 nm, UVC), which induces replication stress and replication fork uncoupling (Byun et al., >>2005<<; Cimprich and Cortez, 2008).
n3:mentions: n2:15833913

Subject Item: _:vb34205049
rdf:type: n3:Context
rdf:value: In addition, treatment of HisC mutant embryos with the ATR inhibitor VE-821 (Prevo et al., >>2012<<) or the Chk1 inhibitor CHIR-124 (Tse et al., 2007) did not result in a release of the cell cycle arrest (Figure 5—figure supplements 3 and 4).
n3:mentions: n2:22825331

Subject Item: _:vb34205050
rdf:type: n3:Context
rdf:value: In addition, treatment of HisC mutant embryos with the ATR inhibitor VE-821 (Prevo et al., 2012) or the Chk1 inhibitor CHIR-124 (Tse et al., >>2007<<) did not result in a release of the cell cycle arrest (Figure 5—figure supplements 3 and 4).
n3:mentions: n2:17255282

Subject Item: _:vb34205051
rdf:type: n3:Context
rdf:value: In addition to DSBs, replicative stress can induce phosphorylation of H2Av (Figure 4—figure supplement 1K–P), either directly by ATR dependent phosphorylation (Ward and Chen, >>2001<<; Joyce et al., 2011) or through interconversion of single-stranded DNA generated at stalled replication forks into DSBs (Cimprich and Cortez, 2008).
n3:mentions: n2:11673449

Subject Item: _:vb34205052
rdf:type: n3:Context
rdf:value: In addition to DSBs, replicative stress can induce phosphorylation of H2Av (Figure 4—figure supplement 1K–P), either directly by ATR dependent phosphorylation (Ward and Chen, 2001; Joyce et al., >>2011<<) or through interconversion of single-stranded DNA generated at stalled replication forks into DSBs (Cimprich and Cortez, 2008).
n3:mentions: n2:22024169

Subject Item: _:vb34205053
rdf:type: n3:Context
rdf:value: the G2 phase into mitosis critically depends on the dephosphorylation and activation of Cyclin/Cdk complexes, which is accomplished by a single gene in Drosophila embryos, encoding the CDC25 phosphatase String (Edgar and O'Farrell, >>1990<<). In wild type, string mRNA accumulates during G2 phase and becomes rapidly degraded after cells exit mitosis (Edgar et al., 1994).
n3:mentions: n2:2199063

Subject Item: _:vb34205054
rdf:type: n3:Context
rdf:value: In wild type, string mRNA accumulates during G2 phase and becomes rapidly degraded after cells exit mitosis (Edgar et al., >>1994<<). string transcription is highly dynamic, dictates the pattern of cell divisions during embryogenesis and is controlled by the activity of developmentally regulated transcription factors binding to cis-regulatory sequences spread over >30
n3:mentions: n2:7720557

Subject Item: _:vb34205055
rdf:type: n3:Context
rdf:value: dictates the pattern of cell divisions during embryogenesis and is controlled by the activity of developmentally regulated transcription factors binding to cis-regulatory sequences spread over >30 kb of the string locus (Edgar et al., >>1994<<). In contrast to wild type embryos which accumulate string mRNA in G215 cells of the dorsal epidermis, HisC mutant embryos failed to accumulate string in the corresponding cells although they showed normal upregulation of string
n3:mentions: n2:7720557

Subject Item: _:vb34205056
rdf:type: n3:Context
rdf:value: It is interesting to note that the pattern of M15 in 2xHis-GU embryos closely resembled the pattern of M16 in wild type embryos (Günesdogan et al., >>2010<<; Figure 6D,H).
n3:mentions: n2:20814422

Subject Item: _:vb34205057
rdf:type: n3:Context
rdf:value: To test this hypothesis, HisC mutant embryos were forced to express string in a striped pattern under the control of the prd-GAL4 driver using the GAL4/UAS system (Brand and Perrimon, >>1993<<), which was visualised by coexpression of a UAS-EYFP transgene.
n3:mentions: n2:8223268

Subject Item: _:vb34205058
rdf:type: n6:Section
dc:title: discussion
n6:contains: _:vb34205068 _:vb34205069 _:vb34205070 _:vb34205071 _:vb34205064 _:vb34205065 _:vb34205066 _:vb34205067 _:vb34205060 _:vb34205061 _:vb34205062 _:vb34205063 _:vb34205059 _:vb34205084 _:vb34205085 _:vb34205086 _:vb34205080 _:vb34205081 _:vb34205082 _:vb34205083 _:vb34205076 _:vb34205077 _:vb34205078 _:vb34205079 _:vb34205072 _:vb34205073 _:vb34205074 _:vb34205075

Subject Item: _:vb34205059
rdf:type: n3:Context
rdf:value: In addition to canonical histones, eukaryotes express histone variants that can replace canonical histones in a specific genomic context (Banaszynski et al., >>2010<<). Our results show that these histone variants do not compensate for the lack of canonical histone synthesis with regard to chromatin assembly and cell cycle progression. This could be due to insufficient expression of variant histones
n3:mentions: n2:21074717

Subject Item: _:vb34205060
rdf:type: n3:Context
rdf:value: promoters as it has been shown for the variant histone H3.3, which can fully replace its canonical counterpart, histone H3, but only if it is expressed from within a histone gene unit like the canonical histone (Hödl and Basler, >>2012<<). Alternatively, it could reflect structural divergence of the histone variants as in the case of His2Av (van Daal et al., 1988) and dBigH1 (Perez-Montero et al., 2013).
n3:mentions: n2:23142044

Subject Item: _:vb34205061
rdf:type: n3:Context
rdf:value: Alternatively, it could reflect structural divergence of the histone variants as in the case of His2Av (van Daal et al., >>1988<<) and dBigH1 (Perez-Montero et al., 2013).
n3:mentions: n2:3137528

Subject Item: _:vb34205062
rdf:type: n3:Context
rdf:value: Alternatively, it could reflect structural divergence of the histone variants as in the case of His2Av (van Daal et al., 1988) and dBigH1 (Perez-Montero et al., >>2013<<). It will be interesting to test whether individual histone mutations, like a mutation in H2B which does not have a variant histone in Drosophila (Talbert et al., 2012), will cause a similar cell cycle arrest as the histone null mutation
n3:mentions: n2:24055651

Subject Item: _:vb34205063
rdf:type: n3:Context
rdf:value: It will be interesting to test whether individual histone mutations, like a mutation in H2B which does not have a variant histone in Drosophila (Talbert et al., >>2012<<), will cause a similar cell cycle arrest as the histone null mutation HisC.
n3:mentions: n2:22650316

Subject Item: _:vb34205064
rdf:type: n3:Context
rdf:value: This observation is in line with studies that targeted either histone chaperones (Hoek and Stillman, 2003; Ye et al., >>2003<<; Nabatiyan and Krude, 2004; Groth et al., 2007; Takami et al., 2007) or histone mRNA through SLBP or FLASH (Zhao et al., 2004; Barcaroli et al., 2006; Mejlvang et al., 2014) to interfere with chromatin assembly in tissue culture cells.
n3:mentions: n2:12620223

Subject Item: _:vb34205065
rdf:type: n3:Context
rdf:value: This observation is in line with studies that targeted either histone chaperones (Hoek and Stillman, 2003; Ye et al., 2003; Nabatiyan and Krude, >>2004<<; Groth et al., 2007; Takami et al., 2007) or histone mRNA through SLBP or FLASH (Zhao et al., 2004; Barcaroli et al., 2006; Mejlvang et al., 2014) to interfere with chromatin assembly in tissue culture cells.
n3:mentions: n2:15024074

Subject Item: _:vb34205066
rdf:type: n3:Context
rdf:value: This observation is in line with studies that targeted either histone chaperones (Hoek and Stillman, 2003; Ye et al., 2003; Nabatiyan and Krude, 2004; Groth et al., >>2007<<; Takami et al., 2007) or histone mRNA through SLBP or FLASH (Zhao et al., 2004; Barcaroli et al., 2006; Mejlvang et al., 2014) to interfere with chromatin assembly in tissue culture cells.
n3:mentions: n2:18096807

Subject Item: _:vb34205067
rdf:type: n3:Context
rdf:value: This observation is in line with studies that targeted either histone chaperones (Hoek and Stillman, 2003; Ye et al., 2003; Nabatiyan and Krude, 2004; Groth et al., 2007; Takami et al., >>2007<<) or histone mRNA through SLBP or FLASH (Zhao et al., 2004; Barcaroli et al., 2006; Mejlvang et al., 2014) to interfere with chromatin assembly in tissue culture cells.
n3:mentions: n2:17065558

Subject Item: _:vb34205068
rdf:type: n3:Context
rdf:value: is in line with studies that targeted either histone chaperones (Hoek and Stillman, 2003; Ye et al., 2003; Nabatiyan and Krude, 2004; Groth et al., 2007; Takami et al., 2007) or histone mRNA through SLBP or FLASH (Zhao et al., >>2004<<; Barcaroli et al., 2006; Mejlvang et al., 2014) to interfere with chromatin assembly in tissue culture cells.
n3:mentions: n2:15546920

Subject Item: _:vb34205069
rdf:type: n3:Context
rdf:value: histone chaperones (Hoek and Stillman, 2003; Ye et al., 2003; Nabatiyan and Krude, 2004; Groth et al., 2007; Takami et al., 2007) or histone mRNA through SLBP or FLASH (Zhao et al., 2004; Barcaroli et al., 2006; Mejlvang et al., >>2014<<) to interfere with chromatin assembly in tissue culture cells. However, previous work on SLBP in multicellular organisms revealed pleiotropic effects (Sullivan et al., 2001; Lanzotti et al., 2002; Pettitt et al., 2002).
n3:mentions: n2:24379417

Subject Item: _:vb34205070
rdf:type: n3:Context
rdf:value: However, previous work on SLBP in multicellular organisms revealed pleiotropic effects (Sullivan et al., >>2001<<; Lanzotti et al., 2002; Pettitt et al., 2002).
n3:mentions: n2:11157774

Subject Item: _:vb34205071
rdf:type: n3:Context
rdf:value: However, previous work on SLBP in multicellular organisms revealed pleiotropic effects (Sullivan et al., 2001; Lanzotti et al., >>2002<<; Pettitt et al., 2002).
n3:mentions: n2:11884612

Subject Item: _:vb34205072
rdf:type: n3:Context
rdf:value: However, previous work on SLBP in multicellular organisms revealed pleiotropic effects (Sullivan et al., 2001; Lanzotti et al., 2002; Pettitt et al., >>2002<<). Our data illustrate that an extension of the S phase duration caused by diminished histone supply allows a faithful completion of S phase and transition from G2 into M phase of the cell cycle. This S phase extension is likely to be
n3:mentions: n2:11865041

Subject Item: _:vb34205073
rdf:type: n3:Context
rdf:value: This S phase extension is likely to be caused by a direct effect of lowered histone availability on replication fork progression (Groth et al., >>2007<<; Mejlvang et al., 2014) and not by a lack of origin firing, although we cannot exclude this possibility completely.
n3:mentions: n2:18096807

Subject Item: _:vb34205074
rdf:type: n3:Context
rdf:value: This S phase extension is likely to be caused by a direct effect of lowered histone availability on replication fork progression (Groth et al., 2007; Mejlvang et al., >>2014<<) and not by a lack of origin firing, although we cannot exclude this possibility completely.
n3:mentions: n2:24379417

Subject Item: _:vb34205075
rdf:type: n3:Context
rdf:value: It was previously shown that postblastodermal development in Drosophila embryos proceeds largely uncoupled from progression through cell cycles 14–16 (Edgar et al., >>1994<<; Meyer et al., 2002).
n3:mentions: n2:7720557

Subject Item: _:vb34205076
rdf:type: n3:Context
rdf:value: It was previously shown that postblastodermal development in Drosophila embryos proceeds largely uncoupled from progression through cell cycles 14–16 (Edgar et al., 1994; Meyer et al., >>2002<<). Therefore, histone availability limits S phase duration and appears to be a critical link between cell division and development.
n3:mentions: n2:11807025

Subject Item: _:vb34205077
rdf:type: n3:Context
rdf:value: This observation is in contrast to previous studies on CAF-1, which found that cells arrest in S phase and accumulate DNA damage (Hoek and Stillman, 2003; Ye et al., >>2003<<). This discrepancy might in part be explained by the fact that histone chaperones also have a direct function in DNA repair (Schöpf et al., 2012); and thus, in the presence of an intact DNA repair/chromatin assembly machinery in HisC
n3:mentions: n2:12620223

Subject Item: _:vb34205078
rdf:type: n3:Context
rdf:value: of a prolonged replication slow down, since it was shown that neither ATM/Chk2 nor ATR/Chk1 are activated as an immediate consequence of histone deprivation but only after prolonged incubation times (>48 hr) (Mejlvang et al., >>2014<<). Based on our DNA quantification experiments, we found that the bulk of DNA replication in HisC mutants is completed by about 2 hr after entry into S phase, which might differ from the timeframe required to develop significant DNA damage.
n3:mentions: n2:24379417

Subject Item: _:vb34205079
rdf:type: n3:Context
rdf:value: Turnover of γH2Av was shown to require the Tip60 chromatin-remodelling complex (Kusch et al., >>2004<<), which may be affected by the altered chromatin structure in HisC mutants.
n3:mentions: n2:15528408

Subject Item: _:vb34205080
rdf:type: n3:Context
rdf:value: Alternatively, H2Av was recently shown to be phosphorylated independent of ATM/ATR by the chromosomal tandem kinase JIL-1 (Jin et al., >>1999<<; Thomas et al., 2014), which may also be influenced by the changed chromatin topology in HisC mutants.
n3:mentions: n2:10445035

Subject Item: _:vb34205081
rdf:type: n3:Context
rdf:value: Alternatively, H2Av was recently shown to be phosphorylated independent of ATM/ATR by the chromosomal tandem kinase JIL-1 (Jin et al., 1999; Thomas et al., >>2014<<), which may also be influenced by the changed chromatin topology in HisC mutants.
n3:mentions: n2:24508391

Subject Item: _:vb34205082
rdf:type: n3:Context
rdf:value: Both, the ATM/Chk2 and ATR/Chk1 checkpoints are known to act on CDC25 phosphatases by phosphorylation and protein destabilization (Bartek and Lukas, >>2007<<) and it was shown in Drosophila that string transcripts accumulate normally in embryos that suffered from DNA damage (Su et al., 2000).
n3:mentions: n2:17303408

Subject Item: _:vb34205083
rdf:type: n3:Context
rdf:value: known to act on CDC25 phosphatases by phosphorylation and protein destabilization (Bartek and Lukas, 2007) and it was shown in Drosophila that string transcripts accumulate normally in embryos that suffered from DNA damage (Su et al., >>2000<<). In contrast, we find that HisC mutant cells fail to accumulate string transcripts when arrested in G2.
n3:mentions: n2:10679321

Subject Item: _:vb34205084
rdf:type: n3:Context
rdf:value: This finding was surprising since it was shown that the temporal and spatial expression pattern of string is essentially unchanged in embryos that are arrested in G2 by mutations in string or in mitotic Cyclins (Edgar et al., >>1994<<). Thus, this difference is likely due to the failure of HisC mutant embryos to assemble chromatin, resulting in a diminished nucleosome density as shown by the presence of excess MNase hypersensitive DNA. Although we cannot rule out that
n3:mentions: n2:7720557

Subject Item: _:vb34205085
rdf:type: n3:Context
rdf:value: in loading of structural components that are required for chromosome condensation and sister chromatid cohesion, like Cohesins and Condensins, which are proposed to require contact to chromatin rather than naked DNA (Bernard et al., >>2001<<; Nonaka et al., 2002; Tada et al., 2011).
n3:mentions: n2:11598266

Subject Item: _:vb34205086
rdf:type: n3:Context
rdf:value: are required for chromosome condensation and sister chromatid cohesion, like Cohesins and Condensins, which are proposed to require contact to chromatin rather than naked DNA (Bernard et al., 2001; Nonaka et al., 2002; Tada et al., >>2011<<).
n3:mentions: n2:21633354

Subject Item: _:vb561040568
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 8
n3:hasRelevantPaperId: n2:18927579

Subject Item: _:vb561040569
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n3:RelevantScore: 4
n3:hasRelevantPaperId: n2:20948314

Subject Item: _:vb561040570
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 4
n3:hasRelevantPaperId: n2:10995386

Subject Item: _:vb561040571
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n3:RelevantScore: 4
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Subject Item: _:vb561040572
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n3:RelevantScore: 3
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Subject Item: _:vb561040574
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n3:RelevantScore: 3
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Subject Item: _:vb561040575
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 3
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Subject Item: _:vb561040576
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 3
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Subject Item: _:vb561040577
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 3
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Subject Item: _:vb561040578
rdf:type: n3:RelevantBibliographicResource
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rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 3
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rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 3
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rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
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rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
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rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
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rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
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rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
n3:hasRelevantPaperId: n2:10648606

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rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
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rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
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rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
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rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
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rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
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Subject Item: _:vb561040591
rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
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n3:RelevantScore: 2
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Subject Item: _:vb561040593
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n3:RelevantScore: 2
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Subject Item: _:vb561040594
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n3:RelevantScore: 2
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Subject Item: _:vb561040595
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n3:RelevantScore: 2
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n3:RelevantScore: 2
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rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
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rdf:type: n3:RelevantBibliographicResource
n3:RelevantScore: 2
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n3:RelevantScore: 2
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rdf:type: n3:RelevantBibliographicResource
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rdf:type: n3:RelevantBibliographicResource
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