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.
Original language | English (US) |
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Pages (from-to) | 2283-2292 |
Number of pages | 10 |
Journal | Experimental Cell Research |
Volume | 313 |
Issue number | 11 |
DOIs | |
State | Published - Jul 1 2007 |
Externally published | Yes |
Keywords
- DNA cross-links
- Diepoxybutane
- Fanconi anemia
- S-phase checkpoint
ASJC Scopus subject areas
- Cell Biology