TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism

DNA lesions encountered by replicative polymerases threaten genome stability and cell cycleprogression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitinligase, in patients with microcephalic primordial dwarfism/Seckel syndrome. We establish that TRAIPrelocalizes to sites of DNA damage where it is required for optimal phosphorylation of H2AX andRPA2 during S-phase in response to UV irradiation, as well as fork progression through UV-inducedDNA lesions. TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP thereforelimit cellular proliferation, providing a potential mechanism for microcephaly and dwarfismphenotypes. Human genetics thus identifies TRAIP as a novel component of the DNA damageresponse to replication-blocking DNA lesions.