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UNIVERSITY OF SOUTHERN CALIFORNIA

M OL ECUL AR & COM PUTAT I ONAL BI OLOGY


COLLOQUIUM SERIES

Katharina Schlacher, PhD


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.