The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair.
basic_science · Level V
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- Record sourced from PubMed, PMID 19965384.
- Also identified by DOI 10.1126/science.1182372 and PMC identifier 2909596.
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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.
Medical subject headings
- DNA Repair
- DNA Replication
- Fanconi Anemia Complementation Group D2 Protein
- Fanconi Anemia Complementation Group Proteins
- Xenopus Proteins