TRMT10A

Overview

TRMT10A (TRNA Methyltransferase Homolog 10A) encodes a tRNA m1G9 methyltransferase; however, its oncologic role is independent of its RNA-modifying activity. TRMT10A functions as an ATM substrate (phosphorylated at Ser28 after ionizing radiation) that scaffolds BRCA1 recruitment to DNA double-strand breaks (DSBs), facilitating homologous recombination (HR) repair. In metastatic castration-resistant prostate cancer (mCRPC), TRMT10A is overexpressed and confers intrinsic resistance to PARP inhibitors by maintaining HR capacity even in the absence of classical BRCA1/2 mutations.

Alterations observed in the corpus

  • Overexpressed in prostate cancer (PCa) and mCRPC relative to normal prostate tissue; somatic amplification or deletion present in 1.22–5.26% of mCRPC cohorts with no recurrent point mutations. High TRMT10A expression predicts shorter overall survival (P=0.014) and Gleason 8–10 disease in a 54-patient mCRPC cohort. PMID:28068672
  • ATM-substrate phosphorylation at Ser28 is required for TRMT10A’s HR-scaffold function; this is distinct from its tRNA methyltransferase catalytic activity. PMID:28068672

Cancer types (linked)

  • PRAD: TRMT10A overexpression is a prognostic marker for shorter OS and higher-grade disease in mCRPC; it confers PARPi resistance by maintaining BRCA1 recruitment to DSBs independently of BRCA1/2 mutation status. PMID:28068672

Co-occurrence and mutual exclusivity

  • TRMT10A expression positively correlated with PALB2, BRCA1, BRCA2, and RAD51 in TCGA prostate samples, suggesting co-regulation as part of an HR gene expression signature. PMID:28068672
  • USP10 stabilizes TRMT10A via deubiquitination; co-overexpression with USP10 is observed in mCRPC tissue. USP10 has ~10% deep deletions in SU2C/PCF mCRPC cohorts. PMID:28068672

Therapeutic relevance

  • High TRMT10A expression predicts intrinsic PARPi (olaparib/rucaparib/niraparib/talazoparib) resistance in mCRPC; TRMT10A IHC is proposed as a predictive biomarker to stratify BRCA1/2-WT patients. PMID:28068672
  • USP10 inhibition with spautin-1 destabilizes TRMT10A, impairs BRCA1 recruitment and RAD51 foci, and synergizes with olaparib (HSA synergy >10 in cell lines; CI=0.76 in 22Rv1 CDX; additive activity in two PDX models). PMID:28068672
  • TRMT10A loss (low expression or USP10 deep-deletion) confers ATR-inhibitor sensitivity, providing an alternative therapeutic strategy. PMID:28068672

Open questions

  • Spautin-1 is a tool compound; no clinical-grade USP10 inhibitor exists; translational dosing and on-target specificity in humans remain to be established. PMID:28068672
  • ATM-loss tumors are not sensitized to PARPi alone by USP10-TRMT10A axis targeting; predictive biomarker development should account for ATM status. PMID:28068672
  • USP10 has multiple substrates (p53, Beclin-1, AMPK); off-target consequences of long-term USP10 inhibition require characterization. PMID:28068672
  • Validation of TRMT10A IHC as a clinical PARPi-response biomarker in external cohorts and prospective studies is required before clinical translation. PMID:28068672

Sources

This page was processed by crosslinker on 2026-05-14.