SLFN11-mediated tRNA regulation induces cell death by disrupting proteostasis in response to DNA-damaging agents.

ABSTRACT: DNA-damaging agents (DDAs) have long been used in cancer therapy. However, the mechanisms by which DDAs induce cell death are not fully understood, and drug resistance remains a major clinical challenge. Schlafen 11 (SLFN11) was identified as the gene most strongly correlated with sensitivity to DDAs based on mRNA expression levels. SLFN11 sensitizes cancer cells to DDAs by cleaving and decreasing tRNALeu(TAA) levels. Elucidating the detailed mechanism by which SLFN11 induces cell death is expected to provide insights into overcoming drug resistance. Here, we show that, upon administration of DDAs, SLFN11 cleaves tRNALeu(TAA), triggering ER stress and protein aggregate formation, leading to cell death regulated by inositol-requiring enzyme 1 alpha (IRE1α). These responses were significantl

SUBMITTER: Iimori Y 

PROVIDER: S-EPMC12350096 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature