PRMT Blockade Induces Defective DNA Replication Stress Response and Synergizes with PARP Inhibition

Authors

Yang Li
Lacey E Dobrolecki
Christina Sallas
Xudong Zhang
Travis D Kerr
Deepa Bisht
Yalong Wang
Sharad Awasthi
Babita Kaundal
Siqi Wu
Weiyi Peng
Marc L Mendillo
Yiling Lu
Collene R Jeter
Guang Peng
Jinsong Liu
Shannon N Westin
Anil K Sood
Michael T Lewis
Jishnu Das
S Stephen Yi
Mark T Bedford
Daniel J McGrail
Nidhi Sahni

Publication Date

12-19-2023

Journal

Cell Reports Medicine

Abstract

Multiple cancers exhibit aberrant protein arginine methylation by both type I arginine methyltransferases, predominately protein arginine methyltransferase 1 (PRMT1) and to a lesser extent PRMT4, and by type II PRMTs, predominately PRMT5. Here, we perform targeted proteomics following inhibition of PRMT1, PRMT4, and PRMT5 across 12 cancer cell lines. We find that inhibition of type I and II PRMTs suppresses phosphorylated and total ATR in cancer cells. Loss of ATR from PRMT inhibition results in defective DNA replication stress response activation, including from PARP inhibitors. Inhibition of type I and II PRMTs is synergistic with PARP inhibition regardless of homologous recombination function, but type I PRMT inhibition is more toxic to non-malignant cells. Finally, we demonstrate that the combination of PARP and PRMT5 inhibition improves survival in both BRCA-mutant and wild-type patient-derived xenografts without toxicity. Taken together, these results demonstrate that PRMT5 inhibition may be a well-tolerated approach to sensitize tumors to PARP inhibition.

Keywords

Humans, Poly(ADP-ribose) Polymerase Inhibitors, Neoplasms, Cell Line, DNA Replication, Arginine, Protein-Arginine N-Methyltransferases, Repressor Proteins

Comments

Supplementary Materials

PMID: 38118413