Loss of FANCC function is associated with failure to inhibit late firing replication origins after DNA cross-linking
- Molecular and Cellular Biology Program, Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA (United States)
- Divisions of Clinical Research and Human Biology, Fred Hutchinson Cancer Research Center (United States)
Fanconi anemia (FA) cells are abnormally sensitive to DNA cross-linking agents with increased levels of apoptosis and chromosomal instability. Defects in eight FA complementation groups inhibit monoubiquitination of FANCD2, and subsequent recruitment of FANCD2 to DNA damage and S-phase-associated nuclear foci. The specific functional defect in repair or response to DNA damage in FA cells remains unknown. Damage-resistant DNA synthesis is present 2.5-5 h after cross-linker treatment of FANCC, FANCA and FANCD2-deficient cells. Analysis of the size distribution of labeled DNA replication strands revealed that diepoxybutane treatment suppressed labeling of early but not late-firing replicons in FANCC-deficient cells. In contrast, normal responses to ionizing radiation were observed in FANCC-deficient cells. Absence of this late S-phase response in FANCC-deficient cells leads to activation of secondary checkpoint responses.
- OSTI ID:
- 20955487
- Journal Information:
- Experimental Cell Research, Vol. 313, Issue 11; Other Information: DOI: 10.1016/j.yexcr.2007.03.034; PII: S0014-4827(07)00159-0; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0014-4827
- Country of Publication:
- United States
- Language:
- English
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