Abstract 591: Improving Cardiovascular Health Through DNA Repair

Abstract

Accumulated DNA damage and oxidative stress play a critical role in the etiology of cardiovascular diseases. Malfunctions of human DNA repair proteins can lead to increased myocardial infarctions, ischemic heart disease, and congestive heart failure. The FANCJ helicase and the BRCA1 tumor suppressor are essential proteins that coordinate the repair of interstrand DNA crosslinks and double-stranded breaks in human cells. Their activities are especially needed in heart muscle, which undergoes tremendous physiological and chemical stress. Our limited understanding of how FANCJ and BRCA1 target damaged DNA structures remains a major barrier to research progress. As an independent investigator, my primary focus is to assess the impact of oxidative DNA damage on cardiovascular health through systematic dissection of the DNA repair pathways maintained by FANCJ and BRCA1. A detailed understanding of these molecular mechanisms would provide new diagnostic and therapeutic strategies to detect and to treat ischemic heart disease and congestive heart failure. Here, we have examined the DNA binding properties of FANCJ and BRCA1 using fluorescence spectroscopy and biolayer interferometry. We have also measured the viabilities of human cardiomyocytes and probed their sensitivity to reactive oxygen species by automated cell counting and single-cell electrophoresis. The DNA binding results, which describe precisely how FANCJ and BRCA1 organize onto damaged DNA sites, are compared with the cell-based analysis to correlate their DNA interaction patterns with cardioprotection. Our future work will utilize this platform to predict the risks of FANCJ and BRCA1 single-nucleotide polymorphisms that still have unknown cardiovascular effects.