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The Fanconi Anemia Pathway Promotes Replication-Dependent DNA Interstrand Cross-Link Repair

Science  18 Dec 2009:
Vol. 326, Issue 5960, pp. 1698-1701
DOI: 10.1126/science.1182372

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Abstract

Fanconi anemia is a human cancer predisposition syndrome caused by mutations in 13 Fanc genes. The disorder is characterized by genomic instability and cellular hypersensitivity to chemicals that generate DNA interstrand cross-links (ICLs). A central event in the activation of the Fanconi anemia pathway is the mono-ubiquitylation of the FANCI-FANCD2 complex, but how this complex confers ICL resistance remains enigmatic. Using a cell-free system, we showed that FANCI-FANCD2 is required for replication-coupled ICL repair in S phase. Removal of FANCD2 from extracts inhibits both nucleolytic incisions near the ICL and translesion DNA synthesis past the lesion. Reversal of these defects requires ubiquitylated FANCI-FANCD2. Our results show that multiple steps of the essential S-phase ICL repair mechanism fail when the Fanconi anemia pathway is compromised.

  • * Present address: Laboratory of Genome Maintenance, The Rockefeller University, New York, NY 10021, USA.

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