Federal Project Grant Award Summary

The University of Southern California received a $506,018 Project Grant award from the National Institute of General Medical Sciences (NIGMS) under the Biomedical Research and Research Training program (CFDA 93.859), effective June 1, 2026, through January 31, 2030. This research project will elucidate the structural and molecular basis of DNA Polymerase Theta (POLθ) functions in DNA repair, with particular focus on understanding how this unique multidomain enzyme mediates error-prone microhomology-mediated end joining (MMEJ), translesion synthesis (TLS), and single-strand gap repair. The research deliverables will include high-resolution structural characterization using X-ray crystallography and cryo-electron microscopy (cryo-EM) to define POLθ's DNA repair mechanisms and identify which enzymatic activities are essential for homologous recombination-deficient (HRD) cancer cell survival.

The project integrates structural biology, biochemistry, and cell biology approaches across three specific aims designed to determine how the polymerase domain performs translesion synthesis across UV-induced lesions, resolve how POLθ promotes microhomology-mediated end joining through structural and functional analysis, and identify which POLθ activities are critical for BRCA2-deficient cell survival using structure-function mutants. The findings will establish a mechanistic framework for exploiting POLθ as a cancer therapeutic target and may inform the rational design of next-generation POLθ inhibitors, supporting the broader goal of advancing disease treatment and prevention through fundamental biomedical research.