Mechanistic insights into translesion synthesis-dependent genome instability

基因组不稳定，特征是DNA突变和其他基因的增加形成

Genome instability, characterized by increased formation of DNA mutations and other genetic modifications, is a causative factor in multiple human diseases including cancer, infectious diseases, and neurodegenerative disorders. The translesion synthesis (TLS) pathway, by means of its low fidelity polymerases, causes mutagenesis by bypassing DNA damages and filling post- replicative DNA gaps; a process principally orchestrated by the REV1 polymerase. Thus, TLS and REV1 are essential components of genome instability that drive the formation of new mutations that then translate into new, and often deleterious cellular functions. Recent discoveries from my laboratory challenge this one-dimensional model and have profound implications for understanding human disease and may offer opportunities to develop new therapeutics. We have discovered that the REV1 polymerase has a broader role in controlling genome instability than originally thought. REV1 regulates autophagy, metabolic processes, mitosis fidelity, and replication stress through rereplication. We have evidence that these additional, previously unrecognized roles of REV1 regulate cellular metabolic choices of autophagy versus senescence in response to different types of DNA damages and as such might control cell death mechanisms. Furthermore, our preliminary data unexpectedly showed that REV1 directly regulates autophagy, mitosis, and rereplication proteins. While these early results are enticing, the fundamentals of these discoveries—how REV1 controls cellular metabolism and participates in mitosis fidelity and rereplication are a black box. The work proposed here will systematically tease apart the mechanistic basis of the new roles of the REV1 polymerase. The goals of this proposal are to determine the mechanisms by which REV1 exercises these newly recognized functions by utilizing novel and cutting-edge tools to ask basic biological questions. Successful completion of our proposed studies will redefine the role of REV1, from an error-prone polymerase that participates in the TLS DNA mutagenesis process to a multi-dimensional regulator that controls disease onset or progression by not only making mutations in DNA, but also by controlling cellular metabolism, mitotic fidelity, and rereplication, central to the genome instability process.