MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites

Pei, Huadong; Zhang, Lindsey; Luo, Kuntian; Qin, Yuxin; Chesi, Marta; Fei, Yueyang; Bergsagel, P. Leif; Wang, Liewei; You, Zhipeng; Lou, Zhenkun

doi:10.1038/nature09658

Cited by 382 publications

(425 citation statements)

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“…In addition, we measured H4K20me2 enrichment at a locus adjacent to a single I‐SceI meganuclease‐induced DSB (Fig EV4D). We could detect increased H4K20me2 levels upon DSB induction in both control and cells with SIRT7 knockdown, as has been reported previously (Pei et al , 2011). Most important, we did not observe differences of H4K20me2 levels upon SIRT7 depletion compared to control (Fig EV4E).…”

Section: Resultssupporting

confidence: 89%

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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Section: Resultssupporting

confidence: 89%

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

et al. 2016

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“…26,27 Histone modification is essential for the establishment and maintenance of transcriptional programs during development and gene dosage alterations of histone modifiers are a known cause of intellectual disability syndromes. 28 The HMT function of WHSC1 has been implicated in diverse biological processes, including early development, 29 cytokine signaling, 30 the DNA damage response 31,32 and class switch recombination. 33 In addition to its functional diversity, WHSC1 has a complex pattern of expression, with the potential to regulate multiple processes during development.…”

Section: Discussionmentioning

confidence: 99%

Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf–Hirschhorn Syndrome

et al. 2013

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Wolf-Hirschhorn syndrome (WHS) is a complex genetic disorder caused by the loss of genomic material from the short arm of chromosome 4. Genotype-phenotype correlation studies indicated that the loss of genes within 4p16.3 is necessary for expression of the core features of the phenotype. Within this region, haploinsufficiency of the genes WHSC1 and LETM1 is thought to be a major contributor to the pathogenesis of WHS. We present clinical findings for three patients with relatively small (o400 kb) de novo interstitial deletions that overlap WHSC1 and LETM1. 3D facial analysis was performed for two of these patients. Based on our findings, we propose that hemizygosity of WHSC1 and LETM1 is associated with a clinical phenotype characterized by growth deficiency, feeding difficulties, and motor and speech delays. The deletion of additional genes nearby WHSC1 and LETM1 does not result in a marked increase in the severity of clinical features, arguing against their haploinsufficiency. The absence of seizures and typical WHS craniofacial findings in our cohort suggest that deletion of distinct or additional 4p16.3 genes is necessary for expression of these features. Altogether, these results show that although loss-offunction for WHSC1 and/or LETM1 contributes to some of the features of WHS, deletion of additional genes is required for the full expression of the phenotype, providing further support that WHS is a contiguous gene deletion disorder.

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“…It was shown that the lysine methyltransferase MMSET is recruited to DNA breaks to locally increase the amount of methylated H4K20 [13]. However, the MMSET-mediated methylation of H4K20 or its localization to DNA breaks is not dependent on RNF8 activity [13]. Hence, the local enrichment of H4K20(me2) triggered by MMSET does not explain the requirement of RNF8 for the recruitment of 53BP1 [5][6][7].…”

mentioning

confidence: 97%

“…Nucleosome stacking may contribute to bury methylated H4K20, but since nucleosomes are highly dynamic structures, even buried sites become accessible for protein binding. It was shown that the lysine methyltransferase MMSET is recruited to DNA breaks to locally increase the amount of methylated H4K20 [13]. However, the MMSET-mediated methylation of H4K20 or its localization to DNA breaks is not dependent on RNF8 activity [13].…”

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confidence: 99%

K48-linked ubiquitination and protein degradation regulate 53BP1 recruitment at DNA damage sites

Mallette

Richard

2012

Cell Res

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Efficient DNA damage sensing and repair is crucial to preserve genomic integrity and failure to detect or repair DNA breaks can cause mutations, contributing to the formation of tumors. One key protein required for mediating DNA repair is the tumor suppressor 53BP1. Recent studies now demonstrate the crucial role of K48-linked ubiquitination and protein degradation for 53BP1 recruitment at sites of DNA damage.The linking of ubiquitin chains to proteins is a multistep process involving three different types of enzymes. First, the ubiquitin-activating enzyme E1 catalyzes the transfer of ubiquitin to the ubiquitin-conjugating enzyme E2, which finally conjugates the ubiquitin moeities to target proteins with E3 ubiquitin ligases. Ubiquitin possesses seven lysine residues (K6, K11, K27, K29, K33, K48 and K63) and an N-terminal methionine (M1) that may be utilized to form poly-ubiquitin chains. The various types of linkage are usually associated with different cellular functions, as K48-linked polyubiquitin chains are involved in proteasomal degradation while K63-linked ubiquitination is a docking site for mediating proteinprotein interactions or conformational changes. While the role of K63-linked ubiquitination in the DNA damage response has been demonstrated [1], the role of K48-polyubiquitin chains and degradation remained unclear until recently.In the budding yeast Saccharomyces cerevisiae, components of the 19S and 20S proteasome are recruited to DNA breaks induced by the HO endonuclease [2] and mutant strains lacking components of the proteasome displayed enhanced radio-sensitivity. In mammalian cells, inhibition of the proteasome causes defects in the recruitment of multiple players of the DNA damage response pathway including phosphorylated ATM, 53BP1, NBS1, BRCA1, FANCD2 and RAD51 [3]. Furthermore, depletion of the proteasomal subunits PSMB3 and PSMD4 inhibits the formation of FANCD2 foci following ionizing radiation [3]. In addition, K48-linked polyubiquitin chains accumulate at sites of DNA damage, suggesting a role for protein degradation during the DNA damage response [4]. However, the molecular mechanisms controlling protein ubiquitination and degradation following DNA damage are still unclear. The recent discovery of the ubiquitination cascade triggered by the RING finger E3 ubiquitin ligase RNF8 uncovers a novel pathway responsible for the recruitment of DNA damage effectors. In the presence of DNA breaks, the PI3-like protein kinase ATM phosphorylates the histone variant H2AX on serine 139, creating a docking station for the mediator protein MDC1, which in turn recruits the ubiquitin ligase RNF8 [5][6][7]. RNF8 then stimulates the K63-linked ubiquitination of histones H2A and H2AX neighboring the DNA break. The RNF168 and HERC2 ubiquitin ligases also facilitate the linking of ubiquitin to H2A at damaged sites [8][9][10]. The ubiquitination cascade mediated by RNF8, RNF168 and HERC2 is responsible for the efficient recruitment of RAP80/BRCA1 and 53BP1 to DNA damage foci. The formation of RAP80 foci is...

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MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites

Cited by 382 publications

References 30 publications

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

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

Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf–Hirschhorn Syndrome

K48-linked ubiquitination and protein degradation regulate 53BP1 recruitment at DNA damage sites

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