Dec 16, 2003

Repair kinetics of genomic interstrand DNA cross-links: evidence for DNA double-strand break-dependent activation of the Fanconi anemia/BRCA pathway

Molecular and Cellular Biology
Andreas Rothfuss, Markus Grompe

Abstract

The detailed mechanisms of DNA interstrand cross-link (ICL) repair and the involvement of the Fanconi anemia (FA)/BRCA pathway in this process are not known. Present models suggest that recognition and repair of ICL in human cells occur primarily during the S phase. Here we provide evidence for a refined model in which ICLs are recognized and are rapidly incised by ERCC1/XPF independent of DNA replication. However, the incised ICLs are then processed further and DNA double-strand breaks (DSB) form exclusively in the S phase. FA cells are fully proficient in the sensing and incision of ICL as well as in the subsequent formation of DSB, suggesting a role of the FA/BRCA pathway downstream in ICL repair. In fact, activation of FANCD2 occurs slowly after ICL treatment and correlates with the appearance of DSB in the S phase. In contrast, activation is rapid after ionizing radiation, indicating that the FA/BRCA pathway is specifically activated upon DSB formation. Furthermore, the formation of FANCD2 foci is restricted to a subpopulation of cells, which can be labeled by bromodeoxyuridine incorporation. We therefore conclude that the FA/BRCA pathway, while being dispensable for the early events in ICL repair, is activated in S-phase ...Continue Reading

Mentioned in this Paper

Fanconi Anemia
Biochemical Pathway
Genome
Excision Repair Cross-Complementing 1
ERCC1 gene
Base Excision Repair
FANCD2 gene
Surgical Incisions
Interstrand Cross-link Repair
Fanconi Anemia, Complementation Group A (Disorder)

Related Feeds

Breast Cancer: BRCA1 & BRCA2

Mutations involving BRCA1, found on chromosome 17, and BRCA2, found on chromosome 13, increase the risk for specific cancers, such as breast cancer. Discover the last research on breast cancer BRCA1 and BRCA2 here.