"DNA repair and cell cycle control mechanisms are important guardians against cancerous changes in human cells," says Dr. Richard Kolodner, LICR Member and senior author of the study. "However, the effects of ROS on these cellular responses have not been well characterized. We've now identified a group of genes that cooperate to suppress DNA mutations and the genome rearrangements that are the hallmarks of cancer cells that occur in response to ROS."
Dr. Kolodner and lead author, Meng-Er Huang, generated various yeast strains each with a mutation in the TSA1 gene, which results in increased production of ROS, plus a mutation in one or more genes involved in DNA repair or cell cycle control. Cell survival and accumulation of DNA mutations and gross chromosomal rearrangements in each strain were then analysed to identify genes that cooperate to prevent the deleterious effects of ROS and promote normal cell survival.
"These results suggest that endogenous ROS-induced genome instability may contribute to cancer progression," says Dr. Kolodner, professor of medicine with UCSD School of Medicine and member of the Rebecca and John Moores UCSD Cancer Center. "And increased ROS is almost certainly more harmful in cells with acquired mutations in other genes in the network. However the connections we've found might point to new strategies, like dietary supplements, that will alleviate some of the clinical symptoms of human diseases associated with genetic deficiencies of DNA damage responses."
Journal
Molecular Cell