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Molecular and Cellular Biology, January 2004, p. 123-134, Vol. 24, No. 1
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.1.123-134.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Repair Kinetics of Genomic Interstrand DNA Cross-Links: Evidence for DNA Double-Strand Break-Dependent Activation of the Fanconi Anemia/BRCA Pathway

Andreas Rothfuss* and Markus Grompe

Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon 97239

Received 24 July 2003/ Returned for modification 4 September 2003/ Accepted 23 October 2003

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 cells after DSB have formed.

* Corresponding author. Mailing address: Dept. of Molecular and Medical Genetics, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., L103, Portland, OR 97239. Phone: (503) 494-6888. Fax: (503) 494-6886. E-mail: rothfuss{at}ohsu.edu.

Molecular and Cellular Biology, January 2004, p. 123-134, Vol. 24, No. 1
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.1.123-134.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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