A new non-catalytic role for ubiquitin ligase RNF8 in unfolding higher-order chromatin structure

TY - JOUR

T1 - A new non-catalytic role for ubiquitin ligase RNF8 in unfolding higher-order chromatin structure

AU - Luijsterburg, Martijn S

AU - Acs, Klara

AU - Ackermann, Leena

AU - Wiegant, Wouter W

AU - Bekker-Jensen, Simon

AU - Larsen, Dorthe H

AU - Khanna, Kum Kum

AU - van Attikum, Haico

AU - Mailand, Niels

AU - Dantuma, Nico P

PY - 2012/5/30

Y1 - 2012/5/30

N2 - The ubiquitin ligases RNF8 and RNF168 orchestrate DNA damage signalling through the ubiquitylation of histone H2A and the recruitment of downstream repair factors. Here, we demonstrate that RNF8, but not RNF168 or the canonical H2A ubiquitin ligase RNF2, mediates extensive chromatin decondensation. Our data show that CHD4, the catalytic subunit of the NuRD complex, interacts with RNF8 and is essential for RNF8-mediated chromatin unfolding. The chromatin remodelling activity of CHD4 promotes efficient ubiquitin conjugation and assembly of RNF168 and BRCA1 at DNA double-strand breaks. Interestingly, RNF8-mediated recruitment of CHD4 and subsequent chromatin remodelling were independent of the ubiquitin-ligase activity of RNF8, but involved a non-canonical interaction with the forkhead-associated (FHA) domain. Our study reveals a new mechanism of chromatin remodelling-assisted ubiquitylation, which involves the cooperation between CHD4 and RNF8 to create a local chromatin environment that is permissive to the assembly of checkpoint and repair machineries at DNA lesions.

AB - The ubiquitin ligases RNF8 and RNF168 orchestrate DNA damage signalling through the ubiquitylation of histone H2A and the recruitment of downstream repair factors. Here, we demonstrate that RNF8, but not RNF168 or the canonical H2A ubiquitin ligase RNF2, mediates extensive chromatin decondensation. Our data show that CHD4, the catalytic subunit of the NuRD complex, interacts with RNF8 and is essential for RNF8-mediated chromatin unfolding. The chromatin remodelling activity of CHD4 promotes efficient ubiquitin conjugation and assembly of RNF168 and BRCA1 at DNA double-strand breaks. Interestingly, RNF8-mediated recruitment of CHD4 and subsequent chromatin remodelling were independent of the ubiquitin-ligase activity of RNF8, but involved a non-canonical interaction with the forkhead-associated (FHA) domain. Our study reveals a new mechanism of chromatin remodelling-assisted ubiquitylation, which involves the cooperation between CHD4 and RNF8 to create a local chromatin environment that is permissive to the assembly of checkpoint and repair machineries at DNA lesions.

KW - Animals

KW - Autoantigens

KW - BRCA1 Protein

KW - Cell Line, Tumor

KW - Chromatin

KW - Chromatin Assembly and Disassembly

KW - Cricetinae

KW - DNA Breaks, Double-Stranded

KW - DNA Helicases

KW - DNA-Binding Proteins

KW - Humans

KW - Mi-2 Nucleosome Remodeling and Deacetylase Complex

KW - Mice

KW - Ubiquitin

KW - Ubiquitin-Protein Ligases

KW - Ubiquitination

U2 - 10.1038/emboj.2012.104

DO - 10.1038/emboj.2012.104

M3 - Journal article

C2 - 22531782

SN - 0261-4189

VL - 31

SP - 2511

EP - 2527

JO - E M B O Journal

JF - E M B O Journal

IS - 11

ER -