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FANCD2 binds MCM proteins and controls replisome function upon activation of s phase checkpoint signaling

Gérald Lossaint1, Marion Larroque, Cyril Ribeyre

  • 1Institute of Human Genetics, UPR 1142, CNRS, 141, rue de la Cardonille, 34396 Montpellier, France.

Molecular Cell
|September 3, 2013
PubMed

Insights

Fanconi anemia (FA) proteins like FANCD2 are crucial for genome stability. FANCD2 directly interacts with replication machinery to prevent DNA damage during cell proliferation, thus attenuating cancer risk.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Fanconi anemia (FA) proteins maintain genome stability during cell proliferation.
  • The FA core complex monoubiquitinates FANCD2 and FANCI to activate DNA repair upon replication stress signaling by ATR.

Purpose of the Study:

  • To identify replisome-associated factors involved in DNA repair.
  • To elucidate the role of FANCD2 in genome stability and cell proliferation.

Main Methods:

  • Proteomic screening of replisome-associated factors bound to nascent DNA.
  • Co-immunoprecipitation assays to study protein interactions.
  • Assessment of DNA synthesis, single-stranded DNA accumulation, and senescence markers in human primary cells.

Main Results:

  • FANCD2 and FANCI were identified as replisome-associated factors.
  • FANCD2 directly interacts with minichromosome maintenance (MCM) proteins.
  • ATR signaling promotes FANCD2 association with the MCM2-7 helicase, restraining DNA synthesis and preventing DNA damage and senescence.

Conclusions:

  • FANCD2 acts as an effector of ATR signaling in a surveillance mechanism for DNA replication.
  • This mechanism is essential for maintaining cell proliferation and preventing carcinogenesis.

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