Journal
NATURE GENETICS
Volume 48, Issue 1, Pages 36-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3451
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Funding
- Medical Research Council
- European Research Council (ERC) [281847]
- Lister Institute for Preventative Medicine
- Medical Research Scotland
- German Federal Ministry of Education and Research (BMBF) [01GM1404]
- E-RARE network EuroMicro
- Wellcome Trust
- CMMC
- Cancer Research UK [C17183/A13030, C6/A11224]
- Swiss National Science Foundation [P2ZHP3_158709]
- AIRC [12710]
- EU FP7-PEOPLE [CIG_303806]
- ERC/EU FP7 [HEALTH-F2-2010-259893]
- MRC [MC_PC_U127580972] Funding Source: UKRI
- Cancer Research UK [13030, 11224] Funding Source: researchfish
- Medical Research Council [MC_PC_U127580972] Funding Source: researchfish
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DNA lesions encountered by replicative polymerases threaten genome stability and cell cycle progression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitin ligase, in patients with microcephalic primordial dwarfism. We establish that TRAIP relocalizes to sites of DNA damage, where it is required for optimal phosphorylation of H2AX and RPA2 during S-phase in response to ultraviolet (UV) irradiation, as well as fork progression through UV-induced DNA lesions. TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP therefore limit cellular proliferation, providing a potential mechanism for microcephaly and dwarfism phenotypes. Human genetics thus identifies TRAIP as a component of the DNA damage response to replication-blocking DNA lesions.
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