title: The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage.
abstract: 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.
authors.affiliation: Cancer Research UK, Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham, UK. g.s.stewart@bham.ac.uk
authors.forename: Grant S
authors.initials: GS
authors.lastname: Stewart
authors.forename: Stephanie
authors.initials: S
authors.lastname: Panier
authors.forename: Kelly
authors.initials: K
authors.lastname: Townsend
authors.forename: Abdallah K
authors.initials: AK
authors.lastname: Al-Hakim
authors.forename: Nadine K
authors.initials: NK
authors.lastname: Kolas
authors.forename: Edward S
authors.initials: ES
authors.lastname: Miller
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Nakada
authors.forename: Jarkko
authors.initials: J
authors.lastname: Ylanko
authors.forename: Signe
authors.initials: S
authors.lastname: Olivarius
authors.forename: Megan
authors.initials: M
authors.lastname: Mendez
authors.forename: Ceri
authors.initials: C
authors.lastname: Oldreive
authors.forename: Jan
authors.initials: J
authors.lastname: Wildenhain
authors.forename: Andrea
authors.initials: A
authors.lastname: Tagliaferro
authors.forename: Laurence
authors.initials: L
authors.lastname: Pelletier
authors.forename: Nadine
authors.initials: N
authors.lastname: Taubenheim
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Byrd
authors.forename: Tatjana
authors.initials: T
authors.lastname: Stankovic
authors.forename: A Malcolm R
authors.initials: AM
authors.lastname: Taylor
authors.forename: Daniel
authors.initials: D
authors.lastname: Durocher
mesh_terms: D002460:Cell Line; D004249:DNA Damage; D006657:Histones / Q000378:metabolism; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000378:metabolism*; D011836:Radiation Tolerance; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D006657:Histones; D025801:Ubiquitin; C471607:UBE2N protein, human; D044763:Ubiquitin-Conjugating Enzymes; C535210:RNF168 protein, human; D044767:Ubiquitin-Protein Ligases