Loss of FANCC function is associated with failure to inhibit late firing replication origins after DNA cross-linking

Randall A Phelps; Helene Gingras; David M Hockenbery

doi:10.1016/j.yexcr.2007.03.034

Loss of FANCC function is associated with failure to inhibit late firing replication origins after DNA cross-linking

Exp Cell Res. 2007 Jul 1;313(11):2283-92. doi: 10.1016/j.yexcr.2007.03.034. Epub 2007 Apr 6.

Authors

Randall A Phelps¹, Helene Gingras, David M Hockenbery

Affiliation

¹ Molecular and Cellular Biology Program, Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA, USA.

PMID: 17490643
DOI: 10.1016/j.yexcr.2007.03.034

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.

MeSH terms

Cell Cycle / drug effects
Cell Cycle / genetics
Cell Line
Cross-Linking Reagents / toxicity*
DNA / drug effects
DNA Damage / genetics
DNA Repair / genetics
DNA Replication / genetics*
Epoxy Compounds / toxicity
Fanconi Anemia / genetics*
Fanconi Anemia Complementation Group A Protein / genetics
Fanconi Anemia Complementation Group A Protein / physiology
Fanconi Anemia Complementation Group C Protein / genetics
Fanconi Anemia Complementation Group C Protein / physiology*
Fanconi Anemia Complementation Group D2 Protein / genetics
Fanconi Anemia Complementation Group D2 Protein / physiology
Humans
Oncogene Proteins, Viral / genetics
Oncogene Proteins, Viral / physiology
Replication Origin / genetics*
Repressor Proteins / genetics
Repressor Proteins / physiology
S Phase / drug effects
Tumor Suppressor Protein p53 / metabolism

Substances

Cross-Linking Reagents
E6 protein, Human papillomavirus type 16
Epoxy Compounds
Fanconi Anemia Complementation Group A Protein
Fanconi Anemia Complementation Group C Protein
Fanconi Anemia Complementation Group D2 Protein
Oncogene Proteins, Viral
Repressor Proteins
Tumor Suppressor Protein p53
diepoxybutane
DNA