Loss of FANCC function is associated with failure to inhibit late firing replication origins after DNA cross-linking |
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Authors: | Phelps Randall A Gingras Helene Hockenbery David M |
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Institution: | Molecular and Cellular Biology Program, Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA, USA. |
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Abstract: | 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. |
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Keywords: | Fanconi anemia Diepoxybutane DNA cross-links S-phase checkpoint |
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