53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark

Fradet-Turcotte, Amélie; Canny, Marella D.; Escribano-Díaz, Cristina; Orthwein, Alexandre; Leung, Charles Chung Yun; Huang, Hao; Landry, Marie-Claude; Kitevski-LeBlanc, Julianne L.; Noordermeer, Sylvie M.; Sicheri, Frank; Durocher, Daniel

doi:10.1038/nature12318

Cited by 603 publications

(686 citation statements)

References 40 publications

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“…The current model for 53BP1 recruitment to DNA damage sites mainly involves the recognition of two chromatin marks: H4K20me2 that constitutively interacts with the 53BP1 tudor domain (Botuyan et al , 2006) and H2AK15ub via the 53BP1 UDR motif (Fradet‐Turcotte et al , 2013). 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).…”

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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“…Although the loss of the γ-H2A.X and MDC1 interaction does not affect the initial recruitment of NBS1, 53BP1, and BRCA1, it impairs their retention at DSB-flanking sites (8,9,41,42). 53BP1 recruitment to DSB sites also is regulated by RNF8 and RNF168 ubiquitylation of histones and other proteins at these sites of DNA damage (7,43,44). RNF8 and RNF168 also have been shown to facilitate 53BP1 binding to H4K20me2 at DSB sites (45).…”

Section: Discussionmentioning

confidence: 99%

“…RNF168 ubiquitylates 53BP1 without requiring their localization to DSBs, and this 53BP1 ubiquitylation is required for its initial localization to sites of damage. Once Rnf168 is recruited to DSB sites, its ubiquitylation of H2A on K15 provides an epitope for 53BP1 interaction with chromatin, allowing its retention at these breaks (44). In patients with the RIDDLE syndrome, the defect of these ubiquitylation events mediated by RNF168 is likely to cause the complete absence of 53BP1 IRIF associated with this syndrome (2)(3)(4)(5).…”

Section: Discussionmentioning

confidence: 99%

RNF168 ubiquitylates 53BP1 and controls its response to DNA double-strand breaks

Bohgaki

Ghamrasni

et al. 2013

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

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Defective signaling or repair of DNA double-strand breaks has been associated with developmental defects and human diseases. The E3 ligase RING finger 168 (RNF168), mutated in the human radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties syndrome, was shown to ubiquitylate H2A-type histones, and this ubiquitylation was proposed to facilitate the recruitment of p53-binding protein 1 (53BP1) to the sites of DNA double-strand breaks. In contrast to more upstream proteins signaling DNA double-strand breaks (e.g., RNF8), deficiency of RNF168 fully prevents both the initial recruitment to and retention of 53BP1 at sites of DNA damage; however, the mechanism for this difference has remained unclear. Here, we identify mechanisms that regulate 53BP1 recruitment to the sites of DNA double-strand breaks and provide evidence that RNF168 plays a central role in the regulation of 53BP1 functions. RNF168 mediates K63-linked ubiquitylation of 53BP1 which is required for the initial recruitment of 53BP1 to sites of DNA double-strand breaks and for its function in DNA damage repair, checkpoint activation, and genomic integrity. Our findings highlight the multistep roles of RNF168 in signaling DNA damage.ubiquitin | G2/M checkpoint | HR repair pathways | NHEJ repair pathway T he DNA-damage response (DDR) is critical for genomic integrity (1) and is regulated by posttranslational modifications (PTMs) such as ubiquitylation of histones by the E3 ligases RING finger 8 (RNF8) and RING finger 168 (RNF168). Other PTMs important for DDR include dimethylation of histone H4 (H4K20me2), which allows p53-binding protein 1 (53BP1), a key mediator of DDR, to interact with chromatin.Mutations of RNF168 have been associated with the human radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties (RIDDLE) syndrome, (2-4). RNF168 has an N-terminal RING finger domain, three ubiquitin (Ub)-binding domains (UBDs); two motif interacting with Ub (MIU) domains; and one Ub interacting motif (UIM)-and MIU-related (UMI) UBD (3,5,6). Current data support RNF168 function in DNA double-strand break (DSB) signaling downstream of H2A.X, mediator of DNA damage checkpoint 1 (MDC1), and RNF8 and indicate its requirement for 53BP1 recruitment to DSB sites (3, 5). Through its UBDs, RNF168 recognizes RNF8 ubiquitylated non-nucleosomal protein(s) at DSB-flanking sites, leading to its recruitment at these sites of DNA damage (7). With the Ubconjugating enzyme UBC13, RNF168 initiates ubiquitylation of lysine (K) 13 or 15 of histones H2A and H2A.X, leading to the recruitment of DDR proteins, including 53BP1, to DSBs. Although H2A.X, MDC1, and RNF8 are important for the retention of 53BP1 at these DSBs, its initial and transient recruitment to DNA breaks still occurs in their absence (8-11). In contrast, deficiency of Rnf168 in mouse embryonic fibroblasts (MEFs) completely abolishes 53bp1 recruitment to DSB sites (12). Similar to 53bp1 −/− mice, but in contrast to H2a.x −/− mice (13), young Rnf168 −/− males are ferti...

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“…18,19 53BP1 recognizes dimethylated histone H4 lysine 20 through its Tudor domain and histone H2A K15 monoubiquitinated by RNF168 via a newly identified ubiquitination-dependent recruitment (UDR) motif. 20,21 The ability of 53BP1 to bind efficiently also relies on chromatin reorganization mediated by ubiquitin-dependent removal of specific chromatin proteins in order to reveal dimethylated K20 of histone H4. 22,23 Importantly, chromatin spreading of both BRCA1 and 53BP1 within the vicinity of a DSB is thought to be important for their antagonistic roles in regulating the proper choice between homologous recombination (HR) and nonhomologous end joining (NHEJ) during the cell cycle.…”

Section: Introductionmentioning

confidence: 99%

A small ubiquitin binding domain inhibits ubiquitin-dependent protein recruitment to DNA repair foci

et al. 2013

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53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark

Cited by 603 publications

References 40 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

RNF168 ubiquitylates 53BP1 and controls its response to DNA double-strand breaks

A small ubiquitin binding domain inhibits ubiquitin-dependent protein recruitment to DNA repair foci

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