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Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent genome instability

Christophe Lachaud1, Alberto Moreno2, Francesco Marchesi3

  • 1Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, Scotland, UK.

Science (New York, N.Y.)
|January 23, 2016
PubMed

Insights

Fan1 nuclease recruitment by ubiquitinated Fancd2 is crucial for genome stability. This process prevents chromosome abnormalities during DNA replication fork stalling, even without DNA interstrand cross-links, and Fan1 variants cause cancer-prone phenotypes.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Mono-ubiquitination of Fancd2 is vital for DNA interstrand cross-link (ICL) repair.
  • The Fan1 nuclease is recruited by ubiquitinated Fancd2 to ICLs, suggesting a role in ICL repair mechanisms.

Purpose of the Study:

  • To elucidate the precise role of Fan1 recruitment by ubiquitinated Fancd2 in DNA repair and genome stability.
  • To investigate the function of Fan1 in DNA replication fork progression and its impact on chromosomal integrity.

Main Methods:

  • Utilizing genetic mouse models (Fan1 nuclease-defective knockin mice).
  • Analyzing Fan1 variants in high-risk pancreatic cancer patient samples.
  • Assessing DNA replication fork dynamics and chromosome stability under various conditions.

Main Results:

  • Fan1 recruitment by ubiquitinated Fancd2 is dispensable for ICL repair itself.
  • Fan1 activity is essential for restraining DNA replication fork progression and preventing chromosomal abnormalities during fork stalling, independent of ICLs.
  • Fan1 nuclease-defective mice exhibit increased susceptibility to cancer.
  • A Fan1 variant found in pancreatic cancers disrupts recruitment by ubiquitinated Fancd2, leading to genetic instability without impairing ICL repair.

Conclusions:

  • Fan1 recruitment by ubiquitinated Fancd2 plays a critical role in processing stalled DNA replication forks, which is essential for maintaining genome stability and preventing cancer.
  • The findings highlight a novel function of Fan1 beyond ICL repair, emphasizing its importance in safeguarding genomic integrity during DNA replication stress.

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