The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage.
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.
Stewart
Grant S
GS
Cancer Research UK, Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham, UK. g.s.stewart@bham.ac.uk
Panier
Stephanie
S
Townsend
Kelly
K
Al-Hakim
Abdallah K
AK
Kolas
Nadine K
NK
Miller
Edward S
ES
Nakada
Shinichiro
S
Ylanko
Jarkko
J
Olivarius
Signe
S
Mendez
Megan
M
Oldreive
Ceri
C
Wildenhain
Jan
J
Tagliaferro
Andrea
A
Pelletier
Laurence
L
Taubenheim
Nadine
N
Durandy
Anne
A
Byrd
Philip J
PJ
Stankovic
Tatjana
T
Taylor
A Malcolm R
AM
Durocher
Daniel
D
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
D006657:Histones; D025801:Ubiquitin; C471607:UBE2N protein, human; D044763:Ubiquitin-Conjugating Enzymes; C535210:RNF168 protein, human; D044767:Ubiquitin-Protein Ligases