DDERMMAL, a melanocytic long non-coding RNA, confers DNA damage tolerance to melanoma cells.

Despite remarkable advances in targeted therapies and immunotherapies, a subset of patients fails to respond due to intrinsic resistance, and the majority of those who initially benefit eventually relapse. The emergence of resistant clones under therapeutic pressure has been attributed to both genetic and/or non-genetic resistance mechanisms. Understanding the mechanisms of drug tolerance that drive persistence and resistance, as well as identifying novel biomarkers and therapeutic vulnerabilities, is therefore critically important. Many long non-coding RNAs (lncRNAs) have been implicated in DNA damage; however, their role in melanoma, a malignancy characterized by high mutational rates, remains elusive. Here, we identify the lncRNA DDERMMAL as a modulator of DNA damage response (DDR) signaling. Our findings indicate that DDERMMAL enables melanoma cells to withstand genetic insults while sustaining proliferation, providing a mechanistic basis for lineage-specific persistence under therapeutic pressure and the emergence of de novo mutations driving genetic relapse.