西亚试剂：The Fanconi Anemia Pathway Promotes Replication-Dependent D

发布时间：2025-11-12

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

Puck Knipscheer,1 Markus R?schle,2 Agata Smogorzewska,3,4,* Milica Enoiu,5 The Vinh Ho,6 Orlando D. Sch?rer,5,6 Stephen J. Elledge,3 Johannes C. Walter1,

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.

1 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
2 Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
3 Department of Genetics, Harvard Medical School, and Division of Genetics, Brigham and Women’s Hospital, Boston, MA 02115, USA.
4 Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
5 Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland.
6 Departments of Pharmacological Sciences and Chemistry, Stony Brook University, Stony Brook, NY 11794, USA.

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