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Science. December 18, 2009; 326 (5960): 1698-701.

The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair.

Knipscheer P , Räschle M , Smogorzewska A , Enoiu M , Ho TV , Schärer OD , Elledge SJ , Walter JC .

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.

PubMed ID: 19965384
PMC ID: PMC2909596
Article link: Science.
Grant support: GM62267 NIGMS NIH HHS , T32CA09216 NCI NIH HHSHoward Hughes Medical Institute , R01 GM062267-09 NIGMS NIH HHS , R37 GM044664-23 NIGMS NIH HHS , R01 GM062267 NIGMS NIH HHS , R37 GM044664 NIGMS NIH HHS

Genes referenced: fancd2 fanci

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