PRMT5 Inhibitors Regulate DNA Damage Repair Pathways in Cancer Cells and Improve Response to PARP Inhibition and Chemotherapies.

ABSTRACT: Expression of protein arginine methyltransferase 5 (PRMT5) is highly positively correlated to DNA damage repair (DDR) and DNA replication pathway genes in many types of cancer cells, including ovarian and breast cancer. In the current study, we investigated whether pharmacologic inhibition of PRMT5 downregulates DDR/DNA replication pathway genes and sensitizes cancer cells to chemotherapy and PARP inhibition. Potent and selective PRMT5 inhibitors significantly downregulate expression of multiple DDR and DNA replication genes in cancer cells. Mechanistically, PRMT5 inhibition reduces the presence of PRMT5 and H4R3me2s on promoter regions of DDR genes such as BRCA1/2, RAD51, and ATM. PRMT5 inhibition also promotes global alternative splicing changes. Our data suggest that PRMT5 inhibition re

SUBMITTER: Carter J 

PROVIDER: S-EPMC10627093 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature