A role for the Fanconi anemia C protein in maintaining the DNA damage-induced G2 checkpoint

Brian W. Freie, Samantha L M Ciccone, Xiaxin Li, P. Artur Plett, Christie Orschell, Edward Srour, Helmut Hanenberg, Detlev Schindler, Suk-Hee Lee, D. Clapp

Research output: Contribution to journalArticle

29 Citations (Scopus)

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 -I- 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.

Original languageEnglish
Pages (from-to)50986-50993
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number49
DOIs
StatePublished - Dec 3 2004

Fingerprint

Fanconi Anemia Complementation Group C Protein
Fanconi Anemia Complementation Group Proteins
Protein C
DNA Damage
Fanconi Anemia
DNA
Genomic Instability
Fibroblasts
Cells
Cell Cycle Proteins
Inborn Genetic Diseases
Phosphorylation
Ionizing radiation
Automatic teller machines
Cell Cycle Checkpoints
Ionizing Radiation
DNA Repair
Protein-Tyrosine Kinases
Tyrosine
Repair

ASJC Scopus subject areas

  • Biochemistry

Cite this

A role for the Fanconi anemia C protein in maintaining the DNA damage-induced G2 checkpoint. / Freie, Brian W.; Ciccone, Samantha L M; Li, Xiaxin; Plett, P. Artur; Orschell, Christie; Srour, Edward; Hanenberg, Helmut; Schindler, Detlev; Lee, Suk-Hee; Clapp, D.

In: Journal of Biological Chemistry, Vol. 279, No. 49, 03.12.2004, p. 50986-50993.

Research output: Contribution to journalArticle

Freie, Brian W. ; Ciccone, Samantha L M ; Li, Xiaxin ; Plett, P. Artur ; Orschell, Christie ; Srour, Edward ; Hanenberg, Helmut ; Schindler, Detlev ; Lee, Suk-Hee ; Clapp, D. / A role for the Fanconi anemia C protein in maintaining the DNA damage-induced G2 checkpoint. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 49. pp. 50986-50993.
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AU - Li, Xiaxin

AU - Plett, P. Artur

AU - Orschell, Christie

AU - Srour, Edward

AU - Hanenberg, Helmut

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AU - Clapp, D.

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N2 - 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 -I- 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.

AB - 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 -I- 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.

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