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

Nat Genet. 2016 Jan;48(1):36-43. doi: 10.1038/ng.3451.

Margaret E Harley ^# ¹, Olga Murina ^# ¹, Andrea Leitch ¹, Martin R Higgs ², Louise S Bicknell ¹, Gökhan Yigit ³ ⁴ ⁵, Andrew N Blackford ⁶, Anastasia Zlatanou ², Karen J Mackenzie ¹, Kaalak Reddy ¹, Mihail Halachev ¹, Sarah McGlasson ¹, Martin A M Reijns ¹, Adeline Fluteau ¹, Carol-Anne Martin ¹, Simone Sabbioneda ⁷, Nursel H Elcioglu ⁸, Janine Altmüller ³ ⁹, Holger Thiele ⁹, Lynn Greenhalgh ¹⁰, Luciana Chessa ¹¹, Mohamad Maghnie ¹², Mahmoud Salim ⁸, Michael B Bober ¹³, Peter Nürnberg ⁴ ⁵ ⁹, Stephen P Jackson ⁶ ¹⁴ ¹⁵, Matthew E Hurles ¹⁵, Bernd Wollnik ³ ⁴ ⁵ ¹⁶, Grant S Stewart ², Andrew P Jackson ¹

Affiliations

1 MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK.
2 Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
3 Institute of Human Genetics, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
4 Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
5 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
6 The Gurdon Institute, University of Cambridge, Cambridge, CB2 1QN, UK.
7 Istituto di Genetica Molecolare, CNR, 27100 Pavia, Italy.
8 Department of Pediatric Genetics, Marmara University Pendik Hospital, Istanbul, Turkey.
9 Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany.
10 Cheshire and Merseyside Clinical Genetics Service, Liverpool Women's Hospital, Liverpool, L12 2AP, UK.
11 Department of Clinical and Molecular Medicine, University Sapienza, A.O.S. Andrea, I-00189 Roma, Italy.
12 Department of Pediatrics, IRCCS, Giannina Gaslini, University of Genova, 16147 Genova, Italy.
13 Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware 19803, USA.
14 Department of Biochemistry, University of Cambridge, Cambridge, CB2 1QN, UK.
15 Wellcome Trust Sanger Institute, Cambridge, CB10 1SA, UK.
16 Institute of Human Genetics, University Medical Centre Göttingen, 37073 Göttingen, Germany.
# Contributed equally.

PMID: 26595769 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.

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