from UT MD Anderson Cancer Center Department of Cancer Biology
will present on
"Nuclear and mitochondrial DNA replication
instability by BRCA1/2, p53 and FANC suppressor genes in disease and cancer”
Abstract: Rare hereditary diseases provide a unique window into fundamental
biological processes. The breast cancer susceptibility genes BRCA1/2, p53, and the Fanconi Anemia (FANC) disease suppressor genes function in DNA repair of broken and DNA cross-linked DNA. Yet, these DNA repair functions are insufficient to fully explain the pleotropic patient phenotypes, which include infertility, accelerated aging, congenital abnormalities, increased risk to diabetes, increased risk to cancer, abnormal glucose metabolism and increased inflammation. We defined and will present a new genome stability pathway that we termed “fork protection” involving BRCA1/2 and FANC genes at the DNA replication fork that Friday, February 15, 2019 is genetically and conceptually separable from DNA repair. During fork protection, 2:00 pm to 3:00 pm these genes protect from MRE11-dependent nuclease attack that otherwise causes Ray R. Irani Hall genome instability, a hallmark of cancer. While defects in fork protection can lead 1050 Childs Way, RRI 101 to genome instability associated with tumorigenesis, restoration of fork protection Los Angeles, CA 90089-2910 is a major mechanism for acquisition of chemo-therapy resistance, which is the main cause for cancer-associated death. We further found that p53, which collaborates with BRCA1/2 and is the most frequently mutated tumor suppressor gene, has a function at DNA replication forks that better correlates with its tumor- suppressive function compared to its function in cell-cycle regulation and apoptosis. For additional information, This amongst others is mechanistically reflected in COSMIC mutational signatures contact: of p53 mutant breast cancers. We moreover will present our data on defining BRCA and FANC gene functions in the mitochondria, where we found that these Myron Goodman, PhD genes protect stalled mitochondrial (mt) DNA replication forks from degradation. mgoodman@usc.edu In patient cells, the degraded mtDNA fragments activate a cGAS inflammation Jen Nelson response, that can be attenuated by restoration of fork protection. Collectively, jmbrewer@usc.edu our data provides a molecular explanation for key patient features, and expands our understanding of how defects in nuclear DNA replication instability suppressor genes contribute to diverse hallmarks of cancer and disease.