Journal
CELL
Volume 136, Issue 3, Pages 435-446Publisher
CELL PRESS
DOI: 10.1016/j.cell.2008.12.041
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Funding
- Danish Cancer Society
- Danish National Research Foundation
- European Commission Integrated Projects DNA Repair'' and GENICA,'' Lundbeck Foundation [R13-A1287]
- Danish Research Council
- John and Birthe Meyer Foundation
- German Federal Ministry of Education and Research ( BMBF)
- National Genome Research Network [01GR0403]
- European Commission Integrated Project Mitocheck [FP6-503464]
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DNA double-strand breaks (DSBs) not only interrupt the genetic information, but also disrupt the chromatin structure, and both impairments require repair mechanisms to ensure genome integrity. We showed previously that RNF8-mediated chromatin ubiquitylation protects genome integrity by promoting the accumulation of repair factors at DSBs. Here, we provide evidence that, while RNF8 is necessary to trigger the DSB-associated ubiquitylations, it is not sufficient to sustain conjugated ubiquitin in this compartment. We identified RNF168 as a novel chromatin-associated ubiquitin ligase with an ability to bind ubiquitin. We show that RNF168 interacts with ubiquitylated H2A, assembles at DSBs in an RNF8-dependent manner, and, by targeting H2A and H2AX, amplifies local concentration of lysine 63-linked ubiquitin conjugates to the threshold required for retention of 53BP1 and BRCA1. Thus, RNF168 defines a new pathway involving sequential ubiquitylations on damaged chromosomes and uncovers a functional cooperation between E3 ligases in genome maintenance.
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