Abstract B010: Exploring the synthetic lethal interactions between mRNA methyl-5-cytocine at sites of R-loops and mismatch repair deficiency in solid tumor

Abstract The RNA methyltransferase TRDMT1 generates 5-methyl Cytosine (m5C) at R-loops which promotes transcription coupled homologous recombination (TC-HR) and thus impedes cellular sensitivity to R-loop induced DNA double-strand breaks (DSBs) at transcribing regions of the genome. We performed TRDMT1 inhibitor based drug screening approach in 300 cancer cell lines and identifies key factors associated with DNA mismatch repair (MMR) pathway especially in solid tumors. The R-loop accumulation correlated to severe replication stress and generated more transcription replication conflicts (TRCs) in TRDMT1 and MMR deficient background. Our study revealed synthetic lethal interactions between TRDMT1 and MMR which can provide a promising future strategy for improving treatment of solid tumors. Citation Format: Li Lan. Exploring the synthetic lethal interactions between mRNA methyl-5-cytocine at sites of R-loops and mismatch repair deficiency in solid tumor [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B010.