The p400 ATPase regulates nucleosome stability and chromatin ubiquitination during DNA repair

Xu, Yiming; Sun, Yingli; Jiang, Xiaofeng; Ayrapetov, Marina K.; Moskwa, Patryk; Yang, Shiyong; Weinstock, David M.; Price, Brendan D.

doi:10.1083/jcb.201001160

Cited by 169 publications

(263 citation statements)

References 60 publications

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“…Phosphorylated H2AX (γH2AX) provides a binding site for mdc1, which promotes spreading of γH2AX for hundreds of kilobases either side of the break (1-3). DSBs also promote complex patterns of chromatin ubiquitination, including ubiquitination of H2A/H2AX by the RNF8/RNF168 ubiquitin ligases, which, in turn, creates binding sites for repair proteins such as 53BP1 and brca1 (4)(5)(6)(7). DSBs also lead to increased methylation of histone H3 on lysine 36, which can regulate DNA repair pathway choice (8,9) and methylation of H3 on lysine 9 (10), which drives activation of the Tip60 acetyltransferase and the ATM kinase (11,12).…”

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confidence: 99%

Histone chaperone Anp32e removes H2A.Z from DNA double-strand breaks and promotes nucleosome reorganization and DNA repair

Gürsoy-Yüzügüllü

Ayrapetov

Price

2015

Proc. Natl. Acad. Sci. U.S.A.

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122

155

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The repair of DNA double-strand breaks (DSBs) requires open, flexible chromatin domains. The NuA4–Tip60 complex creates these flexible chromatin structures by exchanging histone H2A.Z onto nucleosomes and promoting acetylation of histone H4. Here, we demonstrate that the accumulation of H2A.Z on nucleosomes at DSBs is transient, and that rapid eviction of H2A.Z is required for DSB repair. Anp32e, an H2A.Z chaperone that interacts with the C-terminal docking domain of H2A.Z, is rapidly recruited to DSBs. Anp32e functions to remove H2A.Z from nucleosomes, so that H2A.Z levels return to basal within 10 min of DNA damage. Further, H2A.Z removal by Anp32e disrupts inhibitory interactions between the histone H4 tail and the nucleosome surface, facilitating increased acetylation of histone H4 following DNA damage. When H2A.Z removal by Anp32e is blocked, nucleosomes at DSBs retain elevated levels of H2A.Z, and assume a more stable, hypoacetylated conformation. Further, loss of Anp32e leads to increased CtIP-dependent end resection, accumulation of single-stranded DNA, and an increase in repair by the alternative nonhomologous end joining pathway. Exchange of H2A.Z onto the chromatin and subsequent rapid removal by Anp32e are therefore critical for creating open, acetylated nucleosome structures and for controlling end resection by CtIP. Dynamic modulation of H2A.Z exchange and removal by Anp32e reveals the importance of the nucleosome surface and nucleosome dynamics in processing the damaged chromatin template during DSB repair.

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confidence: 99%

Histone chaperone Anp32e removes H2A.Z from DNA double-strand breaks and promotes nucleosome reorganization and DNA repair

Gürsoy-Yüzügüllü

Ayrapetov

Price

2015

Proc. Natl. Acad. Sci. U.S.A.

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122

155

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“…Interaction between Tip60 and H3K9me3 (4) promotes acetylation of ATM (5,6,17) and histone H4 (12)(13)(14) by Tip60. Depletion of suv39h1 reduced inducible H3K9me3 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The p84-zinc finger nuclease (p84-ZFN) creates a DSB in intron 1 of the PPP1R12C gene (12,13). PPP1R12C lacks significant H3K9me2/3 but is rich in marks associated with transcription (ENCODE database, http://encodeproject.org/ENCODE/).…”

Section: Resultsmentioning

confidence: 99%

“…For ChIP assays (12,13), cross-linked chromatin was sonicated, and equivalent amounts were incubated with primary antibody and protein G agarose beads precoated with sperm DNA. After washing, immunopurified chromatin was eluted and digested with proteinase K, and purified DNA was quantified by quantitative RT-PCR (RT-qPCR) using the Step One Plus realtime PCR system (Applied Biosystems).…”

Section: Methodsmentioning

confidence: 99%

“…Tip60 also plays a critical role in regulating chromatin structure at DSBs as part of the NuA4-Tip60 complex (11). NuA4-Tip60 catalyzes histone exchange (via the p400 ATPase subunit) and acetylation of histone H4 (by Tip60) at DSBs (12)(13)(14)(15), leading to the formation of open, flexible chromatin domains adjacent to the break (12,13). These open chromatin structures then facilitate histone ubiquitination, the loading of brca1 and 53BP1, and repair of the DSB (13, 16).…”

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confidence: 99%

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DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of repressive chromatin

Ayrapetov

Gürsoy-Yüzügüllü

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Dynamic changes in histone modification are critical for regulating DNA double-strand break (DSB) repair. Activation of the Tip60 acetyltransferase by DSBs requires interaction of Tip60 with histone H3 methylated on lysine 9 (H3K9me3). However, how H3K9 methylation is regulated during DSB repair is not known. Here, we demonstrate that a complex containing kap-1, HP1, and the H3K9 methyltransferase suv39h1 is rapidly loaded onto the chromatin at DSBs. Suv39h1 methylates H3K9, facilitating loading of additional kap-1/HP1/suv39h1 through binding of HP1's chromodomain to the nascent H3K9me3. This process initiates cycles of kap-1/HP1/ suv39h1 loading and H3K9 methylation that facilitate spreading of H3K9me3 and kap-1/HP1/suv39h1 complexes for tens of kilobases away from the DSB. These domains of H3K9me3 function to activate the Tip60 acetyltransferase, allowing Tip60 to acetylate both ataxia telangiectasia-mutated (ATM) kinase and histone H4. Consequently, cells lacking suv39h1 display defective activation of Tip60 and ATM, decreased DSB repair, and increased radiosensitivity. Importantly, activated ATM rapidly phosphorylates kap-1, leading to release of the repressive kap-1/HP1/suv39h1 complex from the chromatin. ATM activation therefore functions as a negative feedback loop to remove repressive suv39h1 complexes at DSBs, which may limit DSB repair. Recruitment of kap-1/HP1/suv39h1 to DSBs therefore provides a mechanism for transiently increasing the levels of H3K9me3 in open chromatin domains that lack H3K9me3 and thereby promoting efficient activation of Tip60 and ATM in these regions. Further, transient formation of repressive chromatin may be critical for stabilizing the damaged chromatin and for remodeling the chromatin to create an efficient template for the DNA repair machinery.histone methylation | homologous recombination D NA double-strand breaks (DSBs) are toxic and must be repaired to maintain genomic stability. Detection of DSBs requires recruitment of the mre11-rad50-nbs1 (MRN) complex to the DNA ends (1). MRN then recruits and activates the ataxia telangiectasia-mutated (ATM) kinase (2, 3) through a mechanism that also requires the Tip60 acetyltransferase (3). Tip60 directly acetylates and activates ATM's kinase activity (4-6) and functions, in combination with MRN, to promote ATM-dependent phosphorylation of DSB repair proteins (3), including histone H2AX. This process creates domains of phosphorylated H2AX (γH2AX) extending for hundreds of kilobases along the chromatin (7,8). Mdc1 then binds to γH2AX, providing a landing pad for other DSB repair proteins, including the RNF8/RNF168 ubiquitin ligases (1, 3, 9, 10). Tip60 also plays a critical role in regulating chromatin structure at DSBs as part of the NuA4-Tip60 complex (11). NuA4-Tip60 catalyzes histone exchange (via the p400 ATPase subunit) and acetylation of histone H4 (by Tip60) at DSBs (12-15), leading to the formation of open, flexible chromatin domains adjacent to the break (12, 13). These open chromatin structures then facilitate histone ub...

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MRGBP, a member of the NuA4 complex, inhibits DNA double‐strand break repair

et al. 2021

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The repair of DNA breaks takes place in the context of chromatin and thus involves the activity of chromatin remodelers. The nucleosome acetyltransferase of H4 (NuA4) remodeler complex enables DNA break repair by relaxing flanking chromatin. Here, we show that MRG domain binding protein (MRGBP), a member of this complex, acts as a general inhibitor of DNA double‐strand break repair. Upon its downregulation, repair is generally increased. This is particularly evident for the stimulation of early events of homologous recombination. Thus, MRGBP has an opposing role to the main catalytic subunits of the NuA4 complex. Our data suggest that MRGBP acts by limiting the activity of this complex in DNA repair, specifically by narrowing the extent of DNA‐end resection.

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The p400 ATPase regulates nucleosome stability and chromatin ubiquitination during DNA repair

Abstract: p400 unwinds chromatin from nucleosomes flanking double-strand breaks to facilitate recruitment of the DNA repair components brca1 and 53BP1.

Cited by 169 publications

References 60 publications

Histone chaperone Anp32e removes H2A.Z from DNA double-strand breaks and promotes nucleosome reorganization and DNA repair

Histone chaperone Anp32e removes H2A.Z from DNA double-strand breaks and promotes nucleosome reorganization and DNA repair

DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of repressive chromatin

MRGBP, a member of the NuA4 complex, inhibits DNA double‐strand break repair

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