Carcinogenesis Advance Access first published online on September 30, 2009
This version published online on October 29, 2009
Carcinogenesis, doi:10.1093/carcin/bgp230
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The human intra-S checkpoint response to UVC-induced DNA damage
Department of Pathology and Laboratory Medicine, Center for Environmental Health and Susceptibility, and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
Email: wkarlk{at}med.unc.edu; phone: 919-966-8209; FAX: 919-966-9673
The intra-S checkpoint response to 254 nm light (UVC)-induced DNA damage appears to have dual functions to slow the rate of DNA synthesis and stabilize replication forks that become stalled at sites of UVC-induced photoproducts in DNA. These functions should provide more time for repair of damaged DNA before its replication and thereby reduce the frequencies of mutations and chromosomal aberrations in surviving cells. This review tries to summarize the history of discovery of the checkpoint, the current state of understanding of the biological features of intra-S checkpoint signaling, and its mechanisms of action with a focus primarily on intra-S checkpoint responses in human cells. The differences in the intra-S checkpoint responses to UVC- and ionizing-radiation (IR)-induced DNA damage are emphasized. Evidence that [6-4]pyrimidine-pyrimidone (6-4PP) photoproducts in DNA trigger the response are discussed and the relationships between cellular responses to UVC and the molecular dose of UVC-induced DNA damage are briefly summarized. The role of the intra-S checkpoint response in protecting against solar radiation carcinogenesis remains to be determined.
Key Words: radiation • DNA replication • initiation • elongation • checkpoint
Received June 22, 2009; revised August 11, 2009; accepted September 15, 2009.