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Recruitment of fanconi anemia and breast cancer proteins to DNA damage sites is differentially governed by replication.

Molecular cell | Sep 11, 2009

Fanconi anemia (FA) is characterized by cellular hypersensitivity to DNA crosslinking agents, but how the Fanconi pathway protects cells from DNA crosslinks and whether FA proteins act directly on crosslinks remain unclear. We developed a chromatin-IP-based strategy termed eChIP and detected association of multiple FA proteins with DNA crosslinks in vivo. Interdependence analyses revealed that crosslink-specific enrichment of various FA proteins is controlled by distinct mechanisms. BRCA-related FA proteins (BRCA2, FANCJ/BACH1, and FANCN/PALB2), but not FA core and I/D2 complexes, require replication for their crosslink association. FANCD2, but not FANCJ and FANCN, requires the FA core complex for its recruitment. FA core complex requires nucleotide excision repair proteins XPA and XPC for its association. Consistent with the distinct recruitment mechanism, recombination-independent crosslink repair was inversely affected in cells deficient of FANC-core versus BRCA-related FA proteins. Thus, FA proteins participate in distinct DNA damage response mechanisms governed by DNA replication status.

Pubmed ID: 19748364 RIS Download

Mesh terms: Apoptosis Regulatory Proteins | BRCA2 Protein | Basic-Leucine Zipper Transcription Factors | Breast Neoplasms | Cell Line, Tumor | Chromatin Immunoprecipitation | Cross-Linking Reagents | DNA Damage | DNA Replication | DNA-Binding Proteins | Fanconi Anemia Complementation Group D2 Protein | Fanconi Anemia Complementation Group Proteins | Female | Ficusin | Gene Expression Regulation, Neoplastic | Humans | Mutation | Nuclear Proteins | Plasmids | Recombination, Genetic | Time Factors | Tumor Suppressor Proteins | Xeroderma Pigmentosum Group A Protein

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Associated grants

  • Agency: NIA NIH HHS, Id: AG000688-07
  • Agency: NIGMS NIH HHS, Id: GM44664
  • Agency: NCI NIH HHS, Id: P01 CA097175
  • Agency: NCI NIH HHS, Id: P01 CA097175-01A20003
  • Agency: NCI NIH HHS, Id: P01 CA097175-059002
  • Agency: NCI NIH HHS, Id: P01-CA97175
  • Agency: NCI NIH HHS, Id: R01 CA091029
  • Agency: NCI NIH HHS, Id: R01 CA091029-04
  • Agency: NCI NIH HHS, Id: R01 CA127945
  • Agency: NCI NIH HHS, Id: R01 CA127945-01A2
  • Agency: NCI NIH HHS, Id: R01 CA138804
  • Agency: NCI NIH HHS, Id: R01 CA138804-01A1
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Intramural NIH HHS, Id:

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