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

Research output: Contribution to journalArticle

  • Andrea Leitch
  • Martin Higgs
  • Goekhan Yigit
  • Andrew Blackford
  • Anastasia Zlatanou
  • Adeline Fluteau
  • Simone Sabbioneda
  • Nursel Elcioglu
  • Janine Altmuller
  • Holger Thiele
  • Lynn Greenhalge
  • Luciana Chessa
  • Mohamad Maghnie
  • Mahmoud Salim
  • Michael B Bober
  • Peter Nurnberg
  • Stephen P Jackson
  • Matthew Hurles
  • Bernd Wollnik
  • Grant S Stewart

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Original languageEnglish
JournalNature Genetics
Early online date25 Nov 2015
Publication statusPublished - Jan 2016


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/Seckel syndrome. 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 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 novel component of the DNA damage
response to replication-blocking DNA lesions.

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