Open AccessThe Fanconi Anemia Pathway Promotes Replication-Dependent DNA Interstrand Cross-Link Repair
Author(s) -
Puck Knipscheer,
Markus Räschle,
Agata Smogorzewska,
Milica Enoiu,
The Vinh Ho,
Orlando D. Schärer,
Stephen J. Elledge,
Johannes C. Walter
Publication year - 2009
Publication title -
science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 12.556
H-Index - 1186
eISSN - 1095-9203
pISSN - 0036-8075
DOI - 10.1126/science.1182372
Subject(s) - fanconi anemia , fancd2 , dna repair , dna damage , genome instability , dna replication , biology , dna , cancer research , microbiology and biotechnology , genetics , chemistry
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.
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