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

TY - JOUR

T1 - Nucleotide excision repair-induced H2A ubiquitination is dependent on MDC1 and RNF8 and reveals a universal DNA damage response

AU - Marteijn, Jurgen A

AU - Bekker-Jensen, Simon

AU - Mailand, Niels

AU - Lans, Hannes

AU - Schwertman, Petra

AU - Gourdin, Audrey M

AU - Dantuma, Nico P

AU - Lukas, Jiri

AU - Vermeulen, Wim

N1 - Keywords: BRCA1 Protein; Cell Cycle Proteins; DNA; DNA Damage; DNA Repair; DNA-Binding Proteins; Dose-Response Relationship, Radiation; Epigenesis, Genetic; Hela Cells; Histones; Humans; Intracellular Signaling Peptides and Proteins; Nuclear Proteins; Protein Processing, Post-Translational; Protein-Serine-Threonine Kinases; RNA Interference; Recombinant Fusion Proteins; Signal Transduction; Time Factors; Trans-Activators; Transfection; Ubiquitin-Conjugating Enzymes; Ubiquitination; Ultraviolet Rays

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

U2 - 10.1083/jcb.200902150

DO - 10.1083/jcb.200902150

M3 - Journal article

C2 - 19797077

SN - 0021-9525

VL - 186

SP - 835

EP - 847

JO - Journal of Cell Biology

JF - Journal of Cell Biology

IS - 6

ER -