A5092737056- DNA Repair Mechanisms
- CRISPR and Genetic Engineering
- PARP inhibition in cancer therapy
- Genetic factors in colorectal cancer
- Enzyme Structure and Function
Lawrence Berkeley National Laboratory
2023-2024
The University of Texas Health Science Center at San Antonio
2024
Abstract Polymerase theta (Polθ) acts in DNA replication and repair, its inhibition is synthetic lethal BRCA1 BRCA2-deficient tumor cells. Novobiocin (NVB) a first-in-class inhibitor of the Polθ ATPase activity, it currently being tested clinical trials as an anti-cancer drug. Here, we investigated molecular mechanism NVB-mediated inhibition. Using hydrogen deuterium exchange-mass spectrometry (HX-MS), biophysical, biochemical, computational cellular assays, found NVB non-competitive ATP...
Abstract Senataxin (SETX), a putative RNA-DNA helicase, is recruited to transcription pause sites via the tumor suppressor BRCA1. Here, we define mechanism by which SETX-BRCA1 resolves transcription-associated R-loops prevent deleterious outcomes. Specifically, show that SETX unwinds R-loops, and complex of BRCA1 its obligatory partner BARD1 binds stimulates R-loop unwinding SETX. Importantly, BRCA1-BARD1 alleviates inhibitory effect RAD52 on SETX-mediated unwinding. We also demonstrate...