title: A role for the Fanconi anemia C protein in maintaining the DNA damage-induced G2 checkpoint.
abstract: 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.affiliation: Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Freie
authors.forename: Samantha L M
authors.initials: SL
authors.lastname: Ciccone
authors.forename: Xiaxin
authors.initials: X
authors.lastname: Li
authors.forename: P Artur
authors.initials: PA
authors.lastname: Plett
authors.forename: Christie M
authors.initials: CM
authors.lastname: Orschell
authors.forename: Edward F
authors.initials: EF
authors.lastname: Srour
authors.forename: Helmut
authors.initials: H
authors.lastname: Hanenberg
authors.forename: Detlev
authors.initials: D
authors.lastname: Schindler
authors.forename: Suk-Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: D Wade
authors.initials: DW
authors.lastname: Clapp
mesh_terms: D000483:Alleles; D000818:Animals; D001973:Bromodeoxyuridine / Q000494:pharmacology; D016203:CDC2 Protein Kinase / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000502:physiology*; D002455:Cell Division; D002460:Cell Line; D002478:Cells, Cultured; D004396:Coloring Agents / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000502:physiology*; D005199:Fanconi Anemia / Q000378:metabolism; D052218:Fanconi Anemia Complementation Group C Protein; D052236:Fanconi Anemia Complementation Group D2 Protein; D051856:Fanconi Anemia Complementation Group Proteins; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D016195:G2 Phase; D006657:Histones / Q000737:chemistry; D006801:Humans; D015151:Immunoblotting; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008938:Mitosis; D009154:Mutation; D009687:Nuclear Proteins / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding; D011839:Radiation, Ionizing; D013997:Time Factors; D019076:Transgenes; D014443:Tyrosine / Q000737:chemistry
chemical_list: D018797:Cell Cycle Proteins; D004396:Coloring Agents; D004268:DNA-Binding Proteins; C497651:FANCC protein, human; C499905:FANCD2 protein, human; C497652:Fancc protein, mouse; C499904:Fancd2 protein, mouse; D052218:Fanconi Anemia Complementation Group C Protein; D052236:Fanconi Anemia Complementation Group D2 Protein; D051856:Fanconi Anemia Complementation Group Proteins; D006657:Histones; D009687:Nuclear Proteins; D014443:Tyrosine; D004247:DNA; D016203:CDC2 Protein Kinase; D001973:Bromodeoxyuridine