Document Detail


A role for the Fanconi anemia C protein in maintaining the DNA damage-induced G2 checkpoint.
MedLine Citation:
PMID:  15377654     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Fanconi anemia (FA) is a complex, heterogeneous genetic disorder composed of at least 11 complementation groups. The FA proteins have recently been found to functionally interact with the cell cycle regulatory proteins ATM and BRCA1; however, the function of the FA proteins in cell cycle control remains incompletely understood. Here we show that the Fanconi anemia complementation group C protein (Fancc) is necessary for proper function of the DNA damage-induced G2/M checkpoint in vitro and in vivo. Despite apparently normal induction of the G2/M checkpoint after ionizing radiation, murine and human cells lacking functional FANCC did not maintain the G2 checkpoint as compared with wild-type cells. The increased rate of mitotic entry seen in Fancc-/-mouse embryo fibroblasts correlated with decreased inhibitory phosphorylation of cdc2 kinase on tyrosine 15. An increased inability to maintain the DNA damage-induced G2 checkpoint was observed in Fancc -/-; Trp53 -/-cells compared with Fancc -/-cells, indicating that Fancc and p53 cooperated to maintain the G2 checkpoint. In contrast, genetic disruption of both Fancc and Atm did not cooperate in the G2 checkpoint. These data indicate that Fancc and p53 in separate pathways converge to regulate the G2 checkpoint. Finally, fibroblasts lacking FANCD2 were found to have a G2 checkpoint phenotype similar to FANCC-deficient cells, indicating that FANCD2, which is activated by the FA complex, was also required to maintain the G2 checkpoint. Because a proper checkpoint function is critical for the maintenance of genomic stability and is intricately related to the function and integrity of the DNA repair process, these data have implications in understanding both the function of FA proteins and the mechanism of genomic instability in FA.
Authors:
Brian W Freie; Samantha L M Ciccone; Xiaxin Li; P Artur Plett; Christie M Orschell; Edward F Srour; Helmut Hanenberg; Detlev Schindler; Suk-Hee Lee; D Wade Clapp
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2004-09-17
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  279     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2004 Dec 
Date Detail:
Created Date:  2004-11-25     Completed Date:  2005-01-11     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  50986-93     Citation Subset:  IM    
Affiliation:
Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
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MeSH Terms
Descriptor/Qualifier:
Alleles
Animals
Bromodeoxyuridine / pharmacology
CDC2 Protein Kinase / metabolism
Cell Cycle Proteins / physiology*
Cell Division
Cell Line
Cells, Cultured
Coloring Agents / pharmacology
DNA / metabolism
DNA Damage*
DNA Repair
DNA-Binding Proteins / physiology*
Fanconi Anemia / metabolism
Fanconi Anemia Complementation Group C Protein
Fanconi Anemia Complementation Group D2 Protein
Fanconi Anemia Complementation Group Proteins
Female
Fibroblasts / metabolism
Flow Cytometry
G2 Phase
Histones / chemistry
Humans
Immunoblotting
Keratinocytes / metabolism
Male
Mice
Mice, Transgenic
Mitosis
Mutation
Nuclear Proteins / physiology*
Phosphorylation
Protein Binding
Radiation, Ionizing
Time Factors
Transgenes
Tyrosine / chemistry
Grant Support
ID/Acronym/Agency:
CA92111/CA/NCI NIH HHS; P50 DK49218/DK/NIDDK NIH HHS; R01 HL063219-04/HL/NHLBI NIH HHS; R01 HL55716/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Cell Cycle Proteins; 0/Coloring Agents; 0/DNA-Binding Proteins; 0/FANCC protein, human; 0/FANCD2 protein, human; 0/Fancc protein, mouse; 0/Fancd2 protein, mouse; 0/Fanconi Anemia Complementation Group C Protein; 0/Fanconi Anemia Complementation Group D2 Protein; 0/Fanconi Anemia Complementation Group Proteins; 0/Histones; 0/Nuclear Proteins; 55520-40-6/Tyrosine; 59-14-3/Bromodeoxyuridine; 9007-49-2/DNA; EC 2.7.11.22/CDC2 Protein Kinase

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