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

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.

SUBMITTER: Knipscheer P 

PROVIDER: S-EPMC2909596 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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

Knipscheer Puck P   Räschle Markus M   Smogorzewska Agata A   Enoiu Milica M   Ho The Vinh TV   Schärer Orlando D OD   Elledge Stephen J SJ   Walter Johannes C JC  

Science (New York, N.Y.) 20091112 5960

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 replic  ...[more]