Involvement of a chromatin remodeling complex in damage tolerance during DNA replication

Falbo, Karina B.; Alabert, Constance; Katou, Yuki; Wu, Shi-Fang; Han, Junhong; Wehr, T; Xiao, Jing; He, Xiangwei; Zhang, Zhiguo; Shi, Yang; Shirahige, Katsuhiko; Pasero, Philippe; Shen, Xuetong

doi:10.1038/nsmb.1686

Cited by 88 publications

(98 citation statements)

References 36 publications

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“…In addition, mIno80 was also required to repress the activation of the ATR-CHK1 pathway. While little is known about how modification of chromatin architecture influences telomere replication, yINO80 has been shown to accumulate at origins of replication to promote the recovery of stalled forks [2,4,30,31]. yINO80 recruits Rad51 to stalled replication forks to mediate the formation of hemicatenated X-shaped DNA structures, which are resolved by the helicase Sgs1 [31].…”

Section: Discussionmentioning

confidence: 99%

“…yINO80 localized to origins of replication, and in response to replication stress, the yINO80 complex has been shown to promote the restart of stalled replication forks [2,4,30]. HDR is required for replication fork restart, and yINO80 has been shown to recruit Rad51 to process recombination intermediates and resolve stalled replication forks [31]. HDR requires resection of DSBs in a 5′-to-3′ manner to ssDNA for the recruitment of proteins critical for checkpoint activation and repair [32], and yINO80 has been shown to promote 5′-to-3′ DNA end resection at DSBs [27,33].…”

Section: Defects In Ssdna Formation and Telomere Replication In Mino8mentioning

confidence: 99%

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The mINO80 chromatin remodeling complex is required for efficient telomere replication and maintenance of genome stability

et al. 2013

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The INO80 (inositol requiring mutant 80) chromatin remodeling complex plays important roles in transcriptional regulation and DNA replication and repair, and consists of several functional protein subunits, including the critical Ino80 ATPase catalytic subunit. While the function of INO80 has been studied in yeast and mammalian cell lines, we do not know how mIno80 contributes to the maintenance of genome stability to prevent cancer development in mice. Here, we use a conditional knockout approach to explore the cellular and organismal functions of mIno80. Deletion of mIno80 results in profound cellular proliferative defects and activation of p21-dependent cellular senescence. While mIno80 is required for efficient repair of DNA double strand breaks, its depletion did not impact upon the formation of γ-H2AX and 53BP1 DNA damage foci, or the activation of the ATM-CHK2-dependent DNA damage response. mIno80 deletion inhibited the generation of single-strand DNA, resulting in defects in homology-directed DNA repair (HDR) at telomeres. Fragile telomeres were prominent in mIno80 ∆/∆ MEFs, suggesting that chromatin remodeling is required for efficient telomere replication. mIno80 −/− mouse embryos die early during embryogenesis, while conditional deletion of mIno80 in adult mice results in weight loss and premature death. In a p53 −/− tumorprone background, mIno80 haploinsufficiency favored the development of sarcomas. Our studies suggest that the mIno80 chromatin remodeling complex plays important roles in telomere replication, HDR-mediated repair of dysfunctional telomeres, and maintenance of genome stability.

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Section: Discussionmentioning

confidence: 99%

Section: Defects In Ssdna Formation and Telomere Replication In Mino8mentioning

confidence: 99%

The mINO80 chromatin remodeling complex is required for efficient telomere replication and maintenance of genome stability

et al. 2013

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“…Although yeast INO80 functions in the stabilization and restarting of stress-induced stalled forks, its role in normal DNA replication remains unclear, with inconsistent results provided by different research groups [7][8][9] . To add complexity, a study reported that yeast INO80 has a specific role in DNA damage tolerance rather than replication fork progression or stability 26 . A study of the human INO80 did not provide evidence for direct involvement in DNA replication 10 .…”

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confidence: 99%

Stabilization and targeting of INO80 to replication forks by BAP1 during normal DNA synthesis

Lee

Lee²,

Hur³

et al. 2014

Nat Commun

103

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The INO80 chromatin-remodelling complex has been implicated in DNA replication during stress in yeast. However, its role in normal DNA replication and its underlying mechanisms remain unclear. Here, we show that INO80 binds to replication forks and promotes fork progression in human cells under unperturbed, normal conditions. We find that Ino80, which encodes the catalytic ATPase of INO80, is essential for mouse embryonic DNA replication and development. Ino80 is recruited to replication forks through interaction with ubiquitinated H2A-aided by BRCA1-associated protein-1 (BAP1), a tumour suppressor and nuclear de-ubiquitinating enzyme that also functions to stabilize Ino80. Importantly, Ino80 is downregulated in BAP1-defective cancer cells due to the lack of an Ino80 stabilization mechanism via BAP1. Our results establish a role for INO80 in normal DNA replication and uncover a mechanism by which this remodeler is targeted to replication forks, suggesting a molecular basis for the tumour-suppressing function of BAP1.

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“…Chromatin reassembly after fork passage and how the chromatin environment contributes to DDT function is only starting to be considered (Falbo et al 2009;Ball et al 2014;Gonzalez-Huici et al 2014;House et al 2014;Kim et al 2014). Our data indicate that the histone acetyltransferase, NuA4, has a role in DDT with a measureable role in error-prone/TLS bypass.…”

Section: Discussionmentioning

confidence: 97%

The NuA4 Complex Promotes Translesion Synthesis (TLS)-Mediated DNA Damage Tolerance

et al. 2015

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Lesions in DNA can block replication fork progression, leading to its collapse and gross chromosomal rearrangements. To circumvent such outcomes, the DNA damage tolerance (DDT) pathway becomes engaged, allowing the replisome to bypass a lesion and complete S phase. Chromatin remodeling complexes have been implicated in the DDT pathways, and here we identify the NuA4 remodeler, which is a histone acetyltransferase, to function on the translesion synthesis (TLS) branch of DDT. Genetic analyses in Saccharomyces cerevisiae showed synergistic sensitivity to MMS when NuA4 alleles, esa1-L254P and yng2D, were combined with the error-free bypass mutant ubc13D. The loss of viability was less pronounced when NuA4 complex mutants were disrupted in combination with error-prone/TLS factors, such as rev3D, suggesting an epistatic relationship between NuA4 and error-prone bypass. Consistent with cellular viability measurements, replication profiles after exposure to MMS indicated that small regions of unreplicated DNA or damage were present to a greater extent in esa1-L254P/ubc13D mutants, which persist beyond the completion of bulk replication compared to esa1-L254P/rev3D. The critical role of NuA4 in error-prone bypass is functional even after the bulk of replication is complete. Underscoring this observation, when Yng2 expression is restricted specifically to G2/M of the cell cycle, viability and TLS-dependent mutagenesis rates were restored. Lastly, disruption of HTZ1, which is a target of NuA4, also resulted in mutagenic rates of reversion on level with esa1-L254P and yng2D mutants, indicating that the histone variant H2A.Z functions in vivo on the TLS branch of DDT. KEYWORDS NuA4; Esa1; Yng2; DNA damage tolerance; H2A.Z C ELLS have evolved mechanisms to repair various types of DNA lesions. However, if damage is present in S phase, then replication forks encountering these obstacles can collapse, resulting in breaks in the genome. To avoid such outcomes, all organisms rely on what are called the DNA damage tolerance (DDT) pathways, which allow bypass of the damage, either by an error-free or an error-prone mechanism. Central to DDT signaling is the ubiquitation (Ub) status of proliferating cell nuclear antigen (PCNA). Both branches require mono-Ub of PCNA on lysine 164 (K164) by Rad6 and Rad18, which are the ubiquitin-conjugating enzyme (E2) and ligase (E3), respectively (Hoege et al. 2002;Stelter and Ulrich 2003). Mono-Ub of K164 promotes error-prone bypass via low-fidelity translesion synthesis (TLS) polymerases, which induce mutagenesis (Lehmann et al. 2007;Ulrich 2007). Mono-Ub PCNA can become poly-Ub via K63 linkage in a reaction mediated by Ubc13-Mms2 and Rad5, and this leads to error-free lesion bypass synthesis using the undamaged newly synthesized strand (template switch) (Branzei and Foiani 2007;Branzei 2011). Both of these pathways allow the completion of replication; however, the initial lesion remains for repair at a future time. The DDT pathway is functional in both S and G2 phases of the cell cycle ...

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Involvement of a chromatin remodeling complex in damage tolerance during DNA replication

Cited by 88 publications

References 36 publications

The mINO80 chromatin remodeling complex is required for efficient telomere replication and maintenance of genome stability

The mINO80 chromatin remodeling complex is required for efficient telomere replication and maintenance of genome stability

Stabilization and targeting of INO80 to replication forks by BAP1 during normal DNA synthesis

The NuA4 Complex Promotes Translesion Synthesis (TLS)-Mediated DNA Damage Tolerance

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