Mutational signatures of DNA damage and repair processes.

DNA in all cells is prone to mutagenesis, with somatic mutations making key contributions to human diseases such as cancer and neurodegenerative diseases, and to aging itself. Mutations are the consequence of exogenous or endogenous mutagenic influences (including radiations and DNA-damaging chemicals) and also result from enzymatic DNA modifications or low fidelity DNA synthesis by specialized DNA polymerases. Mutations are generally prevented by the cellular DNA-repair machinery and defective functioning of this machinery can markedly increase mutation rates. Different mutational processes leave different, characteristic signatures of somatic mutations on the exposed cellular genome. Notably, recent analyses of cancer genomes have revealed several novel mutational signatures, the biological bases of which are predominantly unknown. To define somatic mutational processes operative in cells, and in particular their influences on human disease, we propose to systematically survey, at th e genome-wide level, mutational signatures generated by exposures to known or putative human carcinogens, defective DNA repair/editing processes or dysfunction of other cellular processes. These studies will provide a set of mutational signatures with known underlying causes for subsequent matching to signatures found in normal or diseased human cells and will expand our knowledge of how various cellular components influence mutagenesis.