The biological response to DNA double-strand breaks acts to preserve genome integrity.
Individuals bearing inactivating mutations in components of this response exhibit
clinical symptoms that include cellular radiosensitivity, immunodeficiency, and cancer
predisposition. The archetype for such disorders is Ataxia-Telangiectasia caused by
biallelic mutation in ATM, a central component of the DNA damage response. Here, we
report that the ubiquitin ligase RNF168 is mutated in the RIDDLE syndrome, a recently
discovered immunodeficiency and radiosensitivity disorder. We show that RNF168 is
recruited to sites of DNA damage by binding to ubiquitylated histone H2A. RNF168 acts
with UBC13 to amplify the RNF8-dependent histone ubiquitylation by targeting H2A-type
histones and by promoting the formation of lysine 63-linked ubiquitin conjugates.
These RNF168-dependent chromatin modifications orchestrate the accumulation of 53BP1
and BRCA1 to DNA lesions, and their loss is the likely cause of the cellular and developmental
phenotypes associated with RIDDLE syndrome.