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

Margaret E. Harley, Olga Murina, Andrea Leitch, Martin R. 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 S. Stewart, Andrew P. Jackson

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)36-43
Number of pages8
JournalNature Genetics
Volume48
Issue number1
DOIs
Publication statusPublished - Jan 2016

Keywords

  • Amino Acid Sequence
  • Cell Proliferation
  • Child, Preschool
  • DNA Damage
  • Dwarfism
  • Facies
  • Histones
  • Humans
  • Microcephaly
  • Molecular Sequence Data
  • Mutation
  • Phosphorylation
  • Replication Protein A
  • S Phase
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
  • Ubiquitin-Protein Ligases
  • Ultraviolet Rays
  • Journal Article
  • Research Support, Non-U.S. Gov't

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