Date on Master's Thesis/Doctoral Dissertation
Pharmacology and Toxicology
Pharmacology and Toxicology, MS
Committee Co-Chair (if applicable)
Carcinogenesis; metals; DNA repair; homologous recombination; RAD51
Hexavalent Chromium [Cr(VI)] is a known human lung carcinogen and general health hazard. The mechanism of carcinogenesis remains poorly understood, but chromosome instability (CIN) is the major theory in its carcinogenic mechanism. Homologous recombination (HR) repair is a DNA repair pathway that prevents CIN by repairing DNA double-strand breaks. RAD51, a key mediator protein of HR repair, along with the RAD51 paralogs (RAD51B, C, D, XRCC2, and 3) are required for HR repair. During HR, RAD51 loads and forms a helical nucleoprotein filament structure to promote DNA strand exchange and stimulate pairing activity of DNA. Cr(VI) exposures have been shown to target RAD51 and prevent its loading in lung fibroblasts. The mechanism by which Cr(VI) impacts RAD51 paralogs to cause RAD51 dysfunction remains unknown. In this study, we investigate the effects of Cr(VI) on these paralogs and their complexes in human lung cells. This study found both acute and prolonged Cr(VI) exposure inhibits RAD51D repair response evidenced by decreased RAD51D foci formation, protein levels and gene expression. In contrast, Cr(VI) had minimal effect on XRCC3 repair function, suggesting RAD51D as a part of the BCDX2 complex may be a key initial target in Cr(VI)-induced loss of RAD51 function and HR repair.
Williams, Aggie R., "Particulate hexavalent chromium inhibits homologous recombination repair by targeting RAD51 paralogs in human lung fibroblasts." (2022). Electronic Theses and Dissertations. Paper 3873.