Скачать или смотреть Joann Sweasy - Stress-Induced Mutagenesis: From SOS to the DNA Damage Response

Joann Sweasy, Yale University, Connecticut, CT, United States.

Approximately 50 years ago, at about the same time that nucleotide excision repair was discovered, researchers were curious to understand how cells responded to damage that remained in the DNA and how this damage induced mutations. The SOS hypothesis emerged from studies addressing the responses of cells to ultraviolet (UV) light. It is the first identified coordinated cellular response to stress that arose from connecting apparently disparate phenomena. Escherichia coli (E. coli) strain B was known to be very sensitive to UV light because it formed filaments due to its inability to undergo cell division. Both filament formation and prophage induction occurred in response to UV treatment of E.coli and both were prevented by photoreactivation of pyrimidine dimers. Treatment of E. coli with UV light results in the blockage of DNA replication and also leads to the induction of mutations. The SOS response is now known to be induced as a result of replication stress, namely, single-stranded DNA, leading to the coordinated upregulation of at least 50 genes, including a translesion polymerase. Remarkably, mammalian cells also respond to DNA damage in a highly coordinated manner. This DNA damage response is initiated by transducing signals from stalled replication forks to the cell cycle machinery, which results in halting of the cell cycle. The mammalian DNA damage response regulates hundreds of proteins that are associated with DNA repair, cell death, metabolism, and senescence. Hundreds of chemicals and environmental agents as well as nutrient deprivation induce stress responses that lead to the induction of mutations that result in cancer and other diseases, especially in susceptible individuals. Our future challenges include devising strategies and technologies aimed at identifying individuals who are susceptible to specific cellular stresses along with supporting basic research focused on elucidating the underlying mechanisms of cellular stress responses that promote disease-causing mutations.