Acetylation limits 53BP1 association with damaged chromatin to promote homologous recombination

Tang, Jiang-bo; Cho, Nam Woo; Cui, Gaofeng; Manion, Erica M; Shanbhag, Niraj M.; Botuyan, Maria Victoria; Mer, Georges; Greenberg, Roger A.

doi:10.1038/nsmb.2499

Cited by 462 publications

(638 citation statements)

References 56 publications

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“…Importantly, this process was dependent on CtIP, suggesting that H2A.Z exchange and removal regulates CtIP activity. H2A.Z removal is required for several epigenetic modifications, including H4Ac (5, 13-15) and ubiquitination (5,13,14), which control nucleosome packing and loading of brca1 and 53BP1 at DSBs (5,13,14,48). Consequently, retention of H2A.Z creates more compact nucleosomes lacking key histone modifications, such as H4Ac, at the site of damage.…”

Section: Discussionmentioning

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.

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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Section: Discussionmentioning

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.

122

155

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“…Interestingly, I804-S807 occupies a groove in the second tudor domain composed of E1549, D1550, E1551, K1582 and M1584 (Fig. 4 A and B), the three acidic residues being completely conserved in 53BP1 across all vertebrate species (17). This conservation likely highlights the importance of these residues in the tudor 2 domain for determining substrate specificity.…”

Section: Significancementioning

confidence: 89%

Lysine methylation-dependent binding of 53BP1 to the pRb tumor suppressor

Carr

Munro

Zalmas

et al. 2014

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

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The retinoblastoma tumor suppressor protein pRb is a key regulator of cell cycle progression and mediator of the DNA damage response. Lysine methylation at K810, which occurs within a critical Cdk phosphorylation motif, holds pRb in the hypophosphorylated growth-suppressing state. We show here that methyl K810 is read by the tandem tudor domain containing tumor protein p53 binding protein 1 (53BP1). Structural elucidation of 53BP1 in complex with a methylated K810 pRb peptide emphasized the role of the 53BP1 tandem tudor domain in recognition of the methylated lysine and surrounding residues. Significantly, binding of 53BP1 to methyl K810 occurs on E2 promoter binding factor target genes and allows pRb activity to be effectively integrated with the DNA damage response. Our results widen the repertoire of cellular targets for 53BP1 and suggest a previously unidentified role for 53BP1 in regulating pRb tumor suppressor activity.T he retinoblastoma tumor suppressor protein pRb is either directly mutated or functionally inactivated in the vast majority of human tumors (1). One of its principle roles in cells is to regulate transcription, and the E2 promoter binding factor (E2F) family of transcription factors represents one of its most important targets (2). E2F acts to regulate the expression of a variety of genes connected with cell cycle progression and cell fate (including apoptosis, senescence, and differentiation), and the physical interaction between pRb and E2F hinders transcriptional activation by E2F, which coincides with cell cycle arrest (2, 3).The tumor suppressor activity of pRb and its interaction with E2F is regulated by posttranslational modifications (4). For example, multiple cyclin-dependent kinase (Cdk) phosphorylation events occur within pRb, and pRb phosphorylation is temporally regulated as cells progress through the cell cycle, which disrupts the interaction between pRb and E2F. Other types of modification, such as acetylation in the C-terminal region, are also known to influence pRb activity (5).More recently, a role for lysine (K) methylation in pRb control has been described (6). Thus, residue K810 undergoes methylation mediated by SET [su(var), enhancer-of-zeste, trithorax] domain containing lysine methyltransferase 7 (Set7/9) (also known as SETD7/KMT7) (6). Monomethylation at K810 holds pRb in the hypophosphorylated growth suppressing state, which occurs at a mechanistic level by inhibiting the physical association of Cdk complexes with pRb and thereby blocks Cdk-dependent phosphorylation (6). This is because, in the unmethylated state, K810 acts as the essential basic residue in the Cdk consensus phosphorylation site S807 (namely SPLK, Fig. 1A), which is an early pRb phosphorylation event during cell cycle control (7). Significantly, methylation of K810 hinders recognition and subsequent phosphorylation of S807 by cyclin/ Cdk complexes (6).Here, we have elucidated a previously unidentified level of regulation imposed on pRb mediated by the methylation event at K810. In addition to inhi...

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“…These pathways seem not to be affected in the absence of SIRT7, because we did not observe significant differences between WT and SIRT7‐deficient cells on the amount of MDC1 foci formation at DSB, and the levels of H2A ubiquitination and H4K20me2 (Fig EV4). Interestingly, histone acetylation has been shown to limit 53PBP1 interaction with chromatin (Tang et al , 2013). Increased H4K16Ac levels have been associated with reduced levels of H4K20me2 and therefore reduced 53BP1 recruitment to damaged DNA (Hsiao & Mizzen, 2013; Tang et al , 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, histone acetylation has been shown to limit 53PBP1 interaction with chromatin (Tang et al , 2013). Increased H4K16Ac levels have been associated with reduced levels of H4K20me2 and therefore reduced 53BP1 recruitment to damaged DNA (Hsiao & Mizzen, 2013; Tang et al , 2013). Our results indicate that H3K18Ac also regulates 53BP1 binding to chromatin (Fig 7C–E).…”

Section: Discussionmentioning

confidence: 99%

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

et al. 2016

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Sirtuins, a family of protein deacetylases, promote cellular homeostasis by mediating communication between cells and environment. The enzymatic activity of the mammalian sirtuin SIRT7 targets acetylated lysine in the N‐terminal tail of histone H3 (H3K18Ac), thus modulating chromatin structure and transcriptional competency. SIRT7 deletion is associated with reduced lifespan in mice through unknown mechanisms. Here, we show that SirT7‐knockout mice suffer from partial embryonic lethality and a progeroid‐like phenotype. Consistently, SIRT7‐deficient cells display increased replication stress and impaired DNA repair. SIRT7 is recruited in a PARP1‐dependent manner to sites of DNA damage, where it modulates H3K18Ac levels. H3K18Ac in turn affects recruitment of the damage response factor 53BP1 to DNA double‐strand breaks (DSBs), thereby influencing the efficiency of non‐homologous end joining (NHEJ). These results reveal a direct role for SIRT7 in DSB repair and establish a functional link between SIRT7‐mediated H3K18 deacetylation and the maintenance of genome integrity.

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Acetylation limits 53BP1 association with damaged chromatin to promote homologous recombination

Cited by 462 publications

References 56 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

Lysine methylation-dependent binding of 53BP1 to the pRb tumor suppressor

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

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