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

Margaret E Harley, Olga Murina, Andrea Leitch, Martin Higgs, Louise S Bicknell, Gökhan Yigit, Andrew N Blackford, Anastasia Zlatanou, Karen J Mackenzie, Kaalak Reddy, Mihail Halachev, Sarah McGlasson, Martin A M Reijns, Adeline Fluteau, Carol-Anne Martin, Simone Sabbioneda, Nursel H Elcioglu, Janine Altmüller, Holger Thiele, Lynn GreenhalghLuciana Chessa, Mohamad Maghnie, Mahmoud Salim, Michael B Bober, Peter Nürnberg, Stephen P Jackson, Matthew E Hurles, Bernd Wollnik, Grant Stewart, Andrew Jackson

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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/Seckel syndrome. 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 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 novel component of the DNA damage response to replication-blocking DNA lesions.
Original languageEnglish
Pages (from-to)36-43
Number of pages8
JournalNature Genetics
Issue number1
Early online date23 Nov 2015
Publication statusPublished - Jan 2016


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