Schlacher Laboratory

The Schlacher lab research focuses on understanding molecular mechanisms of nuclear and mitochondrial DNA replication fork stability and their physiological outcomes, including how these processes suppress and direct inflammation, tumorigenesis, disease and drug therapy responses. For this we use single molecule, single cell and in vivo approaches to focus on Fanconi Anemia (FA) suppressor models, which include the BRCA breast cancer suppressors genes. FA is a prototypic cancer pre-dispositioning disease showing the broad spectrum of foundational hallmarks of cancer including high inflammation, genomic instability and metabolic as well as developmental abnormalities. We discovered the pathway of DNA Replication Fork Protection involving the BRCA/FA disease suppressor genes, which are otherwise required for specialized repair of DNA damage. This Replication Fork Protection pathway has subsequently been confirmed to be intricately linked with BRCA/FA cancer suppression functions as well as with drug resistance mechanism in BRCA defective cells. Most recently, we discovered that FA and BRCA proteins are also required in the mitochondria for mitochondrial DNA replication stability, feasibly explaining many of the pleiotropic patient phenotypes important to FA cancer hallmarks that are linked to mitochondrial phenotypes. Importantly, we found that the mitochondrial DNA-dependent instability in FA/BRCA patient cells leads to a distinct cGAS/STAT1 inflammatory signaling that is responsible for inflammation-induced chemotherapy resistance, supporting physiologically distinct importance to this yet unexplored mitochondrial genome stability pathway. We have developed unique Rad51c mouse models overcoming embryonic lethality by having created CRISPR/Cas9 edited hypomorphic Rad51c and polygenic Rad51c+Brca2 mutant mice, which develop cancer and Fanconi Anemia. The overall research plan of the Schlacher laboratory is to obtain an in-depth molecular and physiological understanding of DNA Replication Fork Protection and stability in both the nucleus and the mitochondria to unravel cross-organelle communication during DNA stress and inflammation responses. Our aspiration is that this new knowledge will provide the scientific framework for advanced biomarker development to eventually predict disease predisposition, drug treatment response and develop new treatment strategies based on novel biological understanding and rationale.