The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage

Grant S Stewart, Stephanie Panier, Kelly Townsend, Abdallah K Al-Hakim, Nadine K Kolas, Edward S Miller, Shinichiro Nakada, Jarkko Ylanko, Signe Olivarius, Megan Mendez, Ceri Oldreive, Jan Wildenhain, Andrea Tagliaferro, Laurence Pelletier, Nadine Taubenheim, Anne Durandy, Philip J Byrd, Tatjana Stankovic, A Malcolm R Taylor, Daniel Durocher

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)420-434
Number of pages15
Issue number3
Early online date5 Feb 2009
Publication statusPublished - 6 Feb 2009


  • DNA
  • Signaling


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