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Genetic Factors in Colorectal Cancer / DNA Repair Mechanisms · Journal article
Nature Communications · August 10, 2026
Encouraging direction, but not yet definitive.
This mechanistic study identifies MLH1/PMS2 loss as a determinant of TRDMT1 inhibitor sensitivity and reveals a synthetic lethal interaction between TRDMT1 and MutLα loss driven by transcription-replication conflicts. TRDMT1 inhibition suppresses growth of MLH1-deficient tumors in xenografts, suggesting a potential therapeutic strategy for MutLα-deficient cancers, though clinical translation remains untested.
Mechanistic cell line screening study with in vivo xenograft validation. Cancer cell lines stratified by MLH1 and PMS2 status; MLH1-deficient xenograft tumors in mice. Intervention: TRDMT1 inhibitor (TRDMT1i). Compared with: Untreated or control-treated cell lines and tumors; cells proficient in MMR components.
MLH1 or PMS2 loss identified as key determinants of TRDMT1 inhibitor sensitivity in cancer cell line screening TRDMT1 and MutLα independently recognize DNA–RNA hybrids and cooperatively suppress co-transcriptional R-loops genome-wide in undamaged cells Combined loss of TRDMT1 and MLH1 causes extensive R-loop accumulation and transcription-replication conflicts, impairing replication fork progression and inducing apoptosis-mediated synthetic lethality
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This work identifies MLH1/PMS2-deficient cancers as candidates for TRDMT1 inhibitor therapy via synthetic lethality. However, findings are preclinical; clinical trials are required to evaluate efficacy, safety, and patient stratification in human MLH1-deficient malignancies.
Mechanistic study identifying a synthetic lethal interaction and demonstrating in vivo tumor suppression, but limited to cell lines and xenografts without clinical efficacy data.
As stated by the source record.
Quoted from the source exactly as published.
This work identifies MLH1/PMS2-deficient cancers as candidates for TRDMT1 inhibitor therapy via synthetic lethality. However, findings are preclinical; clinical trials are required to evaluate efficacy, safety, and patient stratification in human MLH1-deficient malignancies.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
Abstract TRDMT1 is an RNA methyltransferase that catalyzes 5-methylcytosine (m5C) formation in R-loops to promote transcription-coupled homologous recombination (TC-HR). Although TRDMT1 inhibition selectively kills BRCA1-deficient cancer cells, broader cancer dependencies on TRDMT1 remain unclear. Here, a TRDMT1 inhibitor (TRDMT1i) sensitivity screen across a large panel of cancer cell lines identifies loss of MLH1 or PMS2, two components of the MutLα mismatch repair (MMR) complex frequently inactivated in tumors, as key determinants of TRDMT1 dependency. In contrast, MutLβ and MutSα/β are dispensable for TRDMT1i resistance, revealing a unique MMR-independent function of MutLα. Mechanistically, TRDMT1 and MutLα independently recognize DNA–RNA hybrids and cooperatively suppress co-transcriptional R-loops genome-wide in undamaged cells, with m5C directing pathway choice. Furthermore, MutLα suppresses R-loops through its ATPase and endonuclease activities and through recruitment of EXO1. Combined loss of TRDMT1 and MLH1 causes extensive R-loop accumulation and transcription replication conflicts (TRCs), impairing replication fork progression, inducing DNA damage, and driving apoptosis-mediated synthetic lethality. Importantly, TRDMT1i suppresses growth of MLH1-deficient tumors by inducing TRCs in vivo, suggesting a potential therapeutic strategy for targeting MutLα-deficient tumors. These studies not only expand our understanding of cancer dependency on TRDMT1, but also identify a promising strategy to exploit TRCs in cancer therapy.
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