Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase

By N. Kolas, J. R. Chapman, Shinichiro Nakada, J. Ylanko, Richard Chahwan, Frédéric D. Sweeney, Stephanie Panier, Megan Mendez, Jan Wildenhain, T. Thomson and 3 more. Science, 2007

955 citations recorded by the source corpus.

Cells respond to DNA double-strand breaks by recruiting factors such as the DNA-damage mediator protein MDC1, the p53-binding protein 1 (53BP1), and the breast cancer susceptibility protein BRCA1 to sites of damaged DNA. Here, we reveal that the ubiquitin ligase RNF8 mediates ubiquitin conjugation and 53BP1 and BRCA1 focal accumulation at sites of DNA lesions. Moreover, we establish that MDC1 recruits RNF8 through phosphodependent interactions between the RNF8 forkhead-associated domain and motifs in MDC1 that are phosphorylated by the DNA-damage activated protein kinase ataxia telangiectasia mutated (ATM). We also show that depletion of the E2 enzyme UBC13 impairs 53BP1 recruitment to sites of damage, which suggests that it cooperates with RNF8. Finally, we reveal that RNF8 promotes the G2/M DNA damage checkpoint and resistance to ionizing radiation. These results demonstrate how the DNA-damage response is orchestrated by ATM-dependent phosphorylation of MDC1 and RNF8-mediated ubiquitination.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/da2a7535e2236d0011c70c21dd61bafab7d02bbf

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Citations in the corpus

Histone ubiquitination: triggering gene activity. (2008, background): “quired for the recruitment of proteins involved in later stages of the response to DNA damage, it remains unclear how ubH2A and ubH2AX are involved in the recruitment of these factors (Huen et al., 2007; Kolas et al., 2007; Mailand et al., 2007).”
Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. (2011, background): “For instance, ATM-dependent phosphorylation of MDC1 on Thr–Gln–X–Phe (TQXF) motifs creates binding sites for the FHA domain of the ubiquitin E3 ligase RNF8 (Ring finger protein 8), which in turn promotes the focal accumulation of 53BP1 and BRCA1 at DSB sites (Huen et al. 2007; Kolas et al. 2007; Mai”
Repair of strand breaks by homologous recombination. (2013, background): “Its accumulation and H2AX phosphorylation (gH2AX) signal the recruitment of MDC1 (Stucki et al. 2005), which in turn recruits 53BP1 (Luijsterburg and van Attikum 2012) and then the E3 ubiquitin ligases, RNF8, RNF168, and BRCA1 (Huen et al. 2007; Kolas et al. 2007; Mailand et al. 2007; Wang and Elled”
DNA damage sensing by the ATM and ATR kinases. (2013, background): “3B) (Huen et al. 2007; Kim et al. 2007a,b; Kolas et al. 2007; Mailand et al. 2007; Sobhian et al. 2007; Wang and Elledge 2007; Wang et al. 2007; Doil et al. 2009; Galanty et al. 2009; Morris et al. 2009; Stewart 2009; Bekker-Jensen et al. 2010; Meerang et al. 2011; Mattiroli et al. 2012).”
An ATM-Dependent Transcriptional Silencing Program is Transmitted Through Chromatin in Cis to DNA Double Strand Breaks (2010, background): “Silence Transcription In cis to DNA Double-Strand Breaks”
RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling. (2012, background): “…with roles in the DNA damage response (DDR) also modify H2A 1182 Cell 150, 1182–1195, September 14, 2012 ª2012 Elsevier Inc. (Doil et al., 2009; Huen et al., 2007; Kolas et al., 2007; Mailand et al., 2007; Marteijn et al., 2009; Pinato et al., 2009; Stewart et al., 2009; Wang and Elledge, 2007).”
The DNA Damage Response: Making it safe to play with knives (2010, background): “…chains generated by RNF8 and RNF168 are recognized by the ubiquitin-interacting motif (UIM) of RAP80, which recruits the BRCA1-A complex, itself an E3 ligase, through the interaction with the scaffold protein ABRA1 (Figure 1A) (Huen et al., 2007; Kolas et al., 2007; Wang and Elledge, 2007).”