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

ISSN
1061-4036
Date Issued
2016
Author(s)
Harley, Margaret E.
Murina, Olga
Leitch, Andrea
Higgs, Martin R.
Bicknell, Louise S.
Blackford, Andrew N.
Zlatanou, Anastasia
Mackenzie, Karen J.
Reddy, Kaalak
Halachev, Mihail
McGlasson, Sarah
Reijns, Martin A. M.
Fluteau, Adeline
Martin, Carol-Anne
Sabbioneda, Simone
Elcioglu, Nursel H.
Altmüller, Janine
Thiele, Holger
Greenhalgh, Lynn
Chessa, Luciana
Maghnie, Mohamad
Salim, Mahmoud
Bober, Michael B.
Nürnberg, Peter
Jackson, Stephen P.
Hurles, Matthew E.
Stewart, Grant S.
Jackson, Andrew P.
DOI
10.1038/ng.3451
Abstract
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.