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Nucleotide excision repair–induced H2A ubiquitination is dependent on MDC1 and RNF8 and reveals a universal DNA damage response

¹ Department of Genetics, Center for Biomedical Genetics, Erasmus Medical Center, 3015 GE Rotterdam, Netherlands
² Center for Genotoxic Stress Research, Institute of Cancer Biology, Danish Cancer Society, DK-2100 Copenhagen, Denmark
³ Department of Cell and Molecular Biology, Karolinska Institute, S-17177 Stockholm, Sweden

Correspondence to Wim Vermeulen: W.Vermeulen{at}erasmusmc.nl

Chromatin modifications are an important component of the of DNA damage response (DDR) network that safeguard genomic integrity. Recently, we demonstrated nucleotide excision repair (NER)–dependent histone H2A ubiquitination at sites of ultraviolet (UV)-induced DNA damage. In this study, we show a sustained H2A ubiquitination at damaged DNA, which requires dynamic ubiquitination by Ubc13 and RNF8. Depletion of these enzymes causes UV hypersensitivity without affecting NER, which is indicative of a function for Ubc13 and RNF8 in the downstream UV–DDR. RNF8 is targeted to damaged DNA through an interaction with the double-strand break (DSB)–DDR scaffold protein MDC1, establishing a novel function for MDC1. RNF8 is recruited to sites of UV damage in a cell cycle–independent fashion that requires NER-generated, single-stranded repair intermediates and ataxia telangiectasia–mutated and Rad3-related protein. Our results reveal a conserved pathway of DNA damage–induced H2A ubiquitination for both DSBs and UV lesions, including the recruitment of 53BP1 and Brca1. Although both lesions are processed by independent repair pathways and trigger signaling responses by distinct kinases, they eventually generate the same epigenetic mark, possibly functioning in DNA damage signal amplification.

Abbreviations used in this paper: 6-4PP, 6-4 photoproduct; ATM, ataxia telangiectasia mutated; ATR, ATM and Rad3-related; CPD, cyclobutane pyrimidine dimer; DDR, DNA damage response; DSB, double-strand break; FHA, forkhead associated; IF, immunofluorescence; IR, ionizing radiation; IRIF, IR-induced foci; LUD, local UV damage; NER, nucleotide excision repair; RPA, replication protein A; shRNA, short hairpin RNA; Ub, ubiquitin; UDS, unscheduled DNA synthesis.

© 2009 Marteijn et al.
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