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

Margaret E Harley1, Olga Murina1, Andrea Leitch1

  • 1MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK.

Nature Genetics
|November 24, 2015
PubMed

Insights

Mutations in TRAIP, an E3 ubiquitin ligase, cause microcephalic primordial dwarfism by impairing DNA damage response and cell proliferation. TRAIP is crucial for genome stability following DNA damage during replication.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • DNA lesions pose a significant threat to genome stability and cell cycle progression.
  • Replicative polymerases can encounter DNA damage, leading to replication stress.

Purpose of the Study:

  • To identify the genetic basis of microcephalic primordial dwarfism.
  • To elucidate the role of TRAIP in the DNA damage response (DDR) and its contribution to human disease phenotypes.

Main Methods:

  • Human genetic analysis to identify mutations in patients.
  • Cellular assays to assess TRAIP localization and function at DNA damage sites.
  • Analysis of DNA repair pathway activation (H2AX, RPA2 phosphorylation) and replication fork progression after UV irradiation.

Main Results:

  • Mutations in TRAIP, encoding an E3 RING ubiquitin ligase, were identified in patients with microcephalic primordial dwarfism.
  • TRAIP was found to relocalize to DNA damage sites and is essential for H2AX and RPA2 phosphorylation during S-phase.
  • TRAIP is required for efficient replication fork progression through UV-induced DNA lesions, and its deficiency limits cellular proliferation.

Conclusions:

  • TRAIP is a critical component of the DNA damage response pathway, specifically addressing replication-blocking DNA lesions.
  • Impaired TRAIP function due to mutations explains the microcephaly and dwarfism observed in affected patients by limiting cellular proliferation.
  • This study highlights the link between DNA repair, genome stability, and human developmental disorders.

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