Mechanistic understanding of cellular responses to genomic stress

Within the past half century we have learned of multiple pathways for repairing damaged DNA, based upon the intrinsic redundancy of information in its complementary double strands. Mechanistic details of these pathways have provided insights into environmental and endogenous threats to genomic stability. Studies on bacterial responses to ultraviolet light led to the discovery of excision repair, as well as the inducible SOS response to DNA damage. Similar responses in eukaryotes promote upregulation of error-prone translesion DNA polymerases. Recent advances in this burgeoning field include duplex DNA sequencing to provide strikingly accurate profiling of mutational signatures, analyses of gene expression patterns in single cells, CRISPR/Cas9 to generate changes at precise genomic positions, novel roles for RNA in gene expression and DNA repair, phase-separated aqueous environments for specialized cellular transactions, and DNA lesions as epigenetic signals for gene expression. The Environmental Mutagenesis and Genomics Society (EMGS), through the broad range of expertise in its membership, stands at the crossroad of basic understanding of mechanisms for genomic maintenance and the field of genetic toxicology, with the need for regulation of exposures to toxic substances. Our future challenges include devising strategies and technologies to identify individuals who are susceptible to specific genomic stresses, along with basic research on the underlying mechanisms of cellular stress responses that promote disease-causing mutations. As the science moves forward it should also be a responsibility for the EMGS to expand its outreach programs for the enlightenment and benefit of all humans and the biosphere. Environ. Mol. Mutagen. 61:25–33, 2020.