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

Autor: Harley ME; MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK., Murina O; MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK., Leitch A; MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK., Higgs MR; Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK., Bicknell LS; MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK., Yigit G; Institute of Human Genetics, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany., Blackford AN; The Gurdon Institute, University of Cambridge, Cambridge, CB2 1QN, UK., Zlatanou A; Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK., Mackenzie KJ; MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK., Reddy K; MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK., Halachev M; MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK., McGlasson S; MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK., Reijns MAM; MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK., Fluteau A; MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK., Martin CA; MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK., Sabbioneda S; Istituto di Genetica Molecolare, CNR, 27100 Pavia, Italy., Elcioglu NH; Department of Pediatric Genetics, Marmara University Pendik Hospital, Istanbul, Turkey., Altmüller J; Institute of Human Genetics, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.; Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany., Thiele H; Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany., Greenhalgh L; Cheshire and Merseyside Clinical Genetics Service, Liverpool Women's Hospital, Liverpool, L12 2AP, UK., Chessa L; Department of Clinical and Molecular Medicine, University Sapienza, A.O.S. Andrea, I-00189 Roma, Italy., Maghnie M; Department of Pediatrics, IRCCS, Giannina Gaslini, University of Genova, 16147 Genova, Italy., Salim M; Department of Pediatric Genetics, Marmara University Pendik Hospital, Istanbul, Turkey., Bober MB; Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware 19803, USA., Nürnberg P; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.; Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany., Jackson SP; The Gurdon Institute, University of Cambridge, Cambridge, CB2 1QN, UK.; Department of Biochemistry, University of Cambridge, Cambridge, CB2 1QN, UK.; Wellcome Trust Sanger Institute, Cambridge, CB10 1SA, UK., Hurles ME; Wellcome Trust Sanger Institute, Cambridge, CB10 1SA, UK., Wollnik B; Institute of Human Genetics, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.; Institute of Human Genetics, University Medical Centre Göttingen, 37073 Göttingen, Germany., Stewart GS; Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK., Jackson AP; MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2016 Jan; Vol. 48 (1), pp. 36-43. Date of Electronic Publication: 2015 Nov 23.
DOI: 10.1038/ng.3451
Abstrakt: 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.
Databáze: MEDLINE