JOURNAL ARTICLE

RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins

Carsten Doil, Niels Mailand, Simon Bekker-Jensen, Patrice Menard, Dorthe Helena Larsen, Rainer Pepperkok, Jan Ellenberg, Stephanie Panier, Daniel Durocher, Jiri Bartek, Jiri Lukas, Claudia Lukas
Cell 2009 February 6, 136 (3): 435-46
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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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