HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes

Bekker‐Jensen, Simon; Danielsen, Jannie Rendtlew; Fugger, Kasper; Gromova, Irina; Nerstedt, Annika; Lukas, Claudia; Bártek, Jiří; Lukáš, Jiří; Mailand, Niels

doi:10.1038/ncb2008

Cited by 241 publications

(256 citation statements)

References 23 publications

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“…Various E2s have been shown to interact with RNF8 to promote ubiquitination (31)(32)(33)(34)(35)59). RNF8 interacts with Ubc13 to ubiquitinate H2A and H2AX at DSB sites (17,36).…”

Section: Discussionmentioning

confidence: 99%

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The RING Finger Protein RNF8 Ubiquitinates Nbs1 to Promote DNA Double-strand Break Repair by Homologous Recombination

Truong

Aslanian

et al. 2012

Journal of Biological Chemistry

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Background:The Mre11-Rad50-Nbs1 (MRN) complex and the ubiquitin E3 ligase RNF8 play important roles in DNA DSB repair. Results: RNF8 interacts with and ubiquitinates Nbs1 to promote binding of Nbs1 to DSBs and HR-mediated DSB repair. Conclusion: Nbs1 ubiquitination by RNF8 is important for Nbs1 recruitment to DSBs and HR-mediated repair of DSBs. Significance: These studies help to understand how ubiquitination modifications contribute to DSB repair and genome stability maintenance in mammalian cells.

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“…Various E2s have been shown to interact with RNF8 to promote ubiquitination (31)(32)(33)(34)(35)59). RNF8 interacts with Ubc13 to ubiquitinate H2A and H2AX at DSB sites (17,36).…”

Section: Discussionmentioning

confidence: 99%

“…RNF8 interacts with Ubc13 and can catalyze Lys-63-linked ubiquitination of H2A and H2AX at DSB sites (30). RNF8 can also interact with other E2s, including UbcH8 and UbcH5C, for mediating the DNA damage response (31)(32)(33)(34)(35). Importantly, RNF8 was found to be critical for localizing BRCA1 to DSBs (17, 36 -38).…”

mentioning

confidence: 99%

The RING Finger Protein RNF8 Ubiquitinates Nbs1 to Promote DNA Double-strand Break Repair by Homologous Recombination

Truong

Aslanian

et al. 2012

Journal of Biological Chemistry

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“…In fact, in response to DSB induction, H2AX is phosphorylated at the Ser139 residue (the phosphorylated H2AX protein being named c-H2AX) by members of the phosphoinositide-3-kinase-related protein kinase family [e.g., ataxia-telangiectasia-mutated (ATM) kinase and the DNAdependent kinase (DNA-PK)] (6). The p53 binding protein 1 (53BP1) functions downstream of a c-H2AX-dependent hierarchy of proteins (e.g., the MRN complex, ATM, and the media-tor of DNA-damage checkpoint 1 protein (MDC1)) that collectively establish IRIF at DSB sites (7)(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Cleavage of the BRCT tandem domains of nibrin by the 657del5 mutation affects the DNA damage response less than the Arg215Trp mutation

et al. 2012

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SummaryThe Nijmegen breakage syndrome (NBS) is a genetic disorder caused by mutations in NBN gene and characterized by chromosomal instability and hypersensitivity to ionizing radiations (IR). The N-terminus of nibrin (NBN) contains a tandem breast cancer 1 (BRCA1) carboxy-terminal (BRCT) domain that represents one of the major mediators of phosphorylation-dependent protein-protein interactions in processes related to cell cycle checkpoint and DNA repair functions. Patients with NBS compound heterozygous for the 657del5 hypomorphic mutation and for the Arg215Trp missense mutation (corresponding to the 643C[T gene mutation) display a clinical phenotype more severe than that of patients homozygous for the 657del5 mutation. Here, we show that both the 657del5 and Arg215Trp mutations, occurring within the tandem BRCT domains of NBN, although not altering the assembly of the MRE11/RAD50/NBN (MRN) complex, affect the MRE11 IR-induced nuclear foci (IRIF) formation and the DNA doublestrand break (DSB) signaling via the phosphorylation of both ataxia-telangiectasia-mutated (ATM) kinase and ATM downstream targets (e.g., SMC1 and p53). Remarkably, data obtained indicate that the cleavage of the BRCT tandem domains of NBN by the 657del5 mutation affects the DNA damage response less than the Arg215Trp mutation. Indeed, the 70-kDa NBN fragment, arising from the 657del5 mutation, maintains the capability to interact with MRE11 and c-H2AX and to form IRIF. Altogether, the role of the tandem BRCT domains of NBN in the localization of the MRN complex at the DNA DSB and in the activation of the damage response is highlighted.

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“…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.…”

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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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HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes

Cited by 241 publications

References 23 publications

The RING Finger Protein RNF8 Ubiquitinates Nbs1 to Promote DNA Double-strand Break Repair by Homologous Recombination

The RING Finger Protein RNF8 Ubiquitinates Nbs1 to Promote DNA Double-strand Break Repair by Homologous Recombination

Cleavage of the BRCT tandem domains of nibrin by the 657del5 mutation affects the DNA damage response less than the Arg215Trp mutation

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

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