Cancer development and progression are fueled by extensive changes in the human genome. Importantly, these deleterious changes can be instigated by isolated catastrophic events, in addition to a gradual accumulation of errors. Understanding the triggers that underpin these catastrophic genetic events will allow us to develop novel strategies to specifically target pathways that cause chromosomal DNA instability in cancer. DNA breaks are induced continuously by agents in our environment and by anti-cancer drugs. While some DNA break repair pathways are accurate, others are error-prone. Over the past two decades, our research shows that an error-prone repair pathway called Break Induced DNA...

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Cancer development and progression are fueled by extensive changes in the human genome. Importantly, these deleterious changes can be instigated by isolated catastrophic events, in addition to a gradual accumulation of errors. Understanding the triggers that underpin these catastrophic genetic events will allow us to develop novel strategies to specifically target pathways that cause chromosomal DNA instability in cancer. DNA breaks are induced continuously by agents in our environment and by anti-cancer drugs. While some DNA break repair pathways are accurate, others are error-prone. Over the past two decades, our research shows that an error-prone repair pathway called Break Induced DNA Replication (BIR) induces clustered genetic mutations and chromosomal rearrangements. Our findings provide the impetus for dissecting how BIR contributes to genomic destabilization that likely fosters cancer development and progression. Collaborating with colleagues at University of Texas Health San Antonio (UTHSA) and Baylor College of Medicine, we will identify the entire repertoire of core BIR protein factors in humans and will use state-of-the-art genetic, biochemical, and structural methods to unravel the mechanistic intricacies of BIR. Working with the Center for Innovative Drug Discovery at UTHSA that is supported by the Cancer Prevention and Research Institute of Texas, we aim to develop inhibitors that target key enzymatic components of the human BIR machinery. Altogether, our studies will help stratify BIR mutational and genomic signatures as an impactful biomarker to guide oncologists in personalized cancer treatment. The chemical inhibitors identified by us will be valuable chemical biology tools for BIR studies and may be developed further into novel cancer therapeutics.

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