Pathway description:
The repair of DNA lesions that occur endogenously or in response to diverse genotoxic stresses is indispensable for genome integrity. DNA lesions activate checkpoint pathways that regulate specific DNA-repair mechanisms in the different phases of the cell cycle. Checkpoint- arrested cells resume cell-cycle progression once damage has been repaired, whereas cells with unrepairable DNA lesions undergo permanent cell-cycle arrest or apoptosis. The G2/M DNA damage checkpoint prevents the cell from entering mitosis (M phase) if the genome is damaged. Environmental DNA-damaging agents include UV light and ionizing radiation. Many of the checkpoint proteins are activated in response to DNA damaged, and a number of phosphorylation events in DNA repair mechanism depend on activation of these kinases. The Mec1/Rad3/ATM/ATR family act early in the checkpoint pathways either as DNA damage detectors or in close association with such detectors. The tumor suppressor P53 is central to the higher eukaryotic checkpoint controls in DNA damage-induced G1 arrest through transcriptional induction of the cyclin-dependent kinases Chk1 and Chk2, and inhibitor p21.Activation of p53 in response to DNA damage and other stresses involves complex posttranslational modification of p53 and its negative modulater MDM2,which is itself induced by p53 at the transcriptional level.
Selected Reviews:
Norbury CJ,Hickson ID.(2001)Cellular responses to DNA damage.Annu Rev Pharmacol Toxicol.41:367-461.
Bartek J,Lukas J.(2003)Chk1 and Chk2 kinases in checkpoint control and cancer.Cancer Cell.3(5)421-9.
Branzei D, Foiani M. (2008)Regulation of DNA repair throughout the cell cycle. Nat Rev Mol Cell Biol. 9(4):297-308.
