Grant R21CA191837

BRCA1 and its cofactor in chemotherapy-associated cardiotoxicity

DESCRIPTION (provided by applicant): With earlier-stage cancer diagnosis and improved efficacy of chemotherapy, doxorubicin-induced cardiotoxicity has increasingly become a significa nt cause of morbidity and mortality among cancer survivors. For example, the cardiac mortality of long-term pediatric cancer survivors is estimated to be more than eight times higher than expected. A major challenge in reducing therapy-associated cardiotoxicity is the paucity of knowledge about the molecular players and pathways that can mitigate the undesired effects of doxorubicin on myocardium. Doxorubicin targets topoisomerase II (Top2) by forming a ternary Top2-doxorubicin-DNA complex, which can lead to DNA breaks and ultimately trigger apoptosis. Mammals have two Top2-encoding genes, Top2??and Top2?. Top2? is overexpressed in dividing cancer cells and most likely serve as a primary target of the antitumor activity of doxorubicin. In contrast, Top2? is expressed in postmitotic cardiomyocytes and mediates the cardiotoxic effect of doxorubicin through its association with promoters of metabolism-related genes. As cardiomyocytes have a high demand for energy production, especially under stressed conditions, it raises the possibility that transcription factors important for energy metabolism-related gene expression may alleviate doxorubicin-induced, Top2?-mediated cardiotoxicity. Cofactor of BRCA1 (COBRA1) is a BRCA1-interacting protein discovered in the PI's lab. It is part of the negative elongation factor (NELF) that regulates transcription through RNA polymerase II (Pol II) pausing. Our preliminary work indicates that COBRA1 in cardiomyocytes plays an important role in sustaining transcription of energy metabolism-related genes. Importantly, cardiomyocyte-specific deletion of COBRA1 or BRCA1 exacerbates doxorubicin-induced cardiotoxicity. Given the physical interaction between BRCA1 and COBRA1, we hypothesize that these two proteins jointly mitigate doxorubicin-induced cardiotoxicity by (1) sustaining transcription of energy metabolism-related genes and (2) counteracting Top2?-mediated genotoxic stress preferentially at the promoters of these genes. Our application is conceptually novel because it explores a previously unappreciated connection between energy metabolism-related transcription and doxorubicin-induced cardiotoxicity. In addition, our proposed work challenges the prevailing DNA repair- centric paradigm for BRCA1 and seeks to elucidate an intriguing functional link between BRCA1/COBRA1 and Pol II pausing in a postmitotic tissue context. By integrating different cutting-edge technologies and aligning historically separate research areas, this trans-disciplinary research team strives to provide insights into a clinically important yet mechanistically under-explored problem in chemo-toxicity and long-term cancer survivorship.