Certain environmental toxins are nucleic acid damaging agents, as are many chemotherapeutics used for cancer therapy. These agents induce various adducts in DNA as well as RNA. Indeed, most of the nucleic acid adducts (>90%) formed due to these chemicals, such as alkylating agents, occur in RNA
Summary A critical question in genome stability is the nature of the chemical damage responsible for repair activation. We previously reported a novel pathway specifically activated during alkylation damage in human cells, where the E3 ubiquitin ligase RNF113A mediates the recruitment of the ASCC repair complex. Yet the mechanistic basis for the alkylation damage selectivity of this pathway remains unclear. Here, we demonstrate that RNA but not DNA alkylation is the initiating signal for this process. Aberrantly methylated RNA is sufficient to recruit ASCC, while an RNA dealkylase suppresses ASCC recruitment during chemical alkylation. This aberrant RNA methylation causes transcriptional repression in a manner dependent on the ASCC complex. We show that an alkylated pre-mRNA, or an RNA containing a single damaged base, is sufficient to activate RNF113A E3 activity in a phosphorylation-dependent manner. Together, our work identifies an unexpected role for RNA damage in eliciting a DNA repair response, and suggests that RNA may serve as the “canary in the coal mine” for sensing alkylation damage.
Abstract Small cell lung cancer (SCLC) is the most fatal form of lung cancer, with dismal survival, limited therapeutic options, and rapid development of chemoresistance. We identified the lysine methyltransferase SMYD3 as a major regulator of SCLC sensitivity to alkylation-based chemotherapy. RNF113A methylation by SMYD3 impairs its interaction with the phosphatase PP4, controlling its phosphorylation levels. This cross-talk between posttranslational modifications acts as a key switch in promoting and maintaining RNF113A E3 ligase activity, essential for its role in alkylation damage response. In turn, SMYD3 inhibition restores SCLC vulnerability to alkylating chemotherapy. Our study sheds light on a novel role of SMYD3 in cancer, uncovering this enzyme as a mediator of alkylation damage sensitivity and providing a rationale for small-molecule SMYD3 inhibition to improve responses to established chemotherapy. Significance: SCLC rapidly becomes resistant to conventional chemotherapy, leaving patients with no alternative treatment options. Our data demonstrate that SMYD3 upregulation and RNF113A methylation in SCLC are key mechanisms that control the alkylation damage response. Notably, SMYD3 inhibition sensitizes cells to alkylating agents and promotes sustained SCLC response to chemotherapy. This article is highlighted in the In This Issue feature, p. 2007
