title: TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism.
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.
authors.affiliation: MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Harley
authors.affiliation: MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK.
authors.forename: Olga
authors.initials: O
authors.lastname: Murina
authors.affiliation: MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Leitch
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Higgs
authors.affiliation: MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK.
authors.forename: Louise S
authors.initials: LS
authors.lastname: Bicknell
authors.affiliation: 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.
authors.forename: Gökhan
authors.initials: G
authors.lastname: Yigit
authors.affiliation: The Gurdon Institute, University of Cambridge, Cambridge, CB2 1QN, UK.
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Blackford
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Zlatanou
authors.affiliation: MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK.
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Mackenzie
authors.affiliation: MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK.
authors.forename: Kaalak
authors.initials: K
authors.lastname: Reddy
authors.affiliation: MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK.
authors.forename: Mihail
authors.initials: M
authors.lastname: Halachev
authors.affiliation: MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: McGlasson
authors.affiliation: MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK.
authors.forename: Martin A M
authors.initials: MAM
authors.lastname: Reijns
authors.affiliation: MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK.
authors.forename: Adeline
authors.initials: A
authors.lastname: Fluteau
authors.affiliation: MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK.
authors.forename: Carol-Anne
authors.initials: CA
authors.lastname: Martin
authors.affiliation: Istituto di Genetica Molecolare, CNR, 27100 Pavia, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Sabbioneda
authors.affiliation: Department of Pediatric Genetics, Marmara University Pendik Hospital, Istanbul, Turkey.
authors.forename: Nursel H
authors.initials: NH
authors.lastname: Elcioglu
authors.affiliation: Institute of Human Genetics, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.|Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Cheshire and Merseyside Clinical Genetics Service, Liverpool Women's Hospital, Liverpool, L12 2AP, UK.
authors.forename: Lynn
authors.initials: L
authors.lastname: Greenhalgh
authors.affiliation: Department of Clinical and Molecular Medicine, University Sapienza, A.O.S. Andrea, I-00189 Roma, Italy.
authors.forename: Luciana
authors.initials: L
authors.lastname: Chessa
authors.affiliation: Department of Pediatrics, IRCCS, Giannina Gaslini, University of Genova, 16147 Genova, Italy.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Maghnie
authors.affiliation: Department of Pediatric Genetics, Marmara University Pendik Hospital, Istanbul, Turkey.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Salim
authors.affiliation: Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware 19803, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Bober
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: 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.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Jackson
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, CB10 1SA, UK.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.affiliation: 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.
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Grant S
authors.initials: GS
authors.lastname: Stewart
authors.affiliation: MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Jackson
mesh_terms: D000595:Amino Acid Sequence; D049109:Cell Proliferation / Q000235:genetics; D002675:Child, Preschool; D004249:DNA Damage / Q000528:radiation effects; D004392:Dwarfism / Q000235:genetics*; D019066:Facies; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008831:Microcephaly / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D051716:Replication Protein A / Q000378:metabolism; D016196:S Phase / Q000528:radiation effects; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: C468783:H2AX protein, human; D006657:Histones; D051716:Replication Protein A; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; C000607340:TRAIP protein, human; D044767:Ubiquitin-Protein Ligases; C516794:RPA2 protein, human