Epitranscriptomic RNA modifications in cancer DNA damage response: mechanistic links between RNA fate, genome maintenance, and therapy resistance

Abstract

Epitranscriptomic RNA modifications have emerged as a fundamental regulatory layer linking RNA metabolism with genome maintenance, DNA damage response (DDR), and therapeutic resistance during cancer evolution. Throughout tumorigenesis, persistent oncogenic signaling, replication stress, oxidative stress, metabolic reprogramming, chronic inflammation, and anticancer treatments continuously generate DNA lesions that challenge genome integrity. Although the DDR network normally safeguards genomic stability by coordinating DNA damage sensing, checkpoint activation, and repair pathway selection, established cancer cells frequently hijack these protective mechanisms to survive radiotherapy, platinum-based chemotherapy, poly(ADP-ribose) polymerase (PARP) inhibitors, and other genotoxic therapies. Increasing evidence indicates that epitranscriptomic regulation is an integral component of the DDR rather than merely a downstream consequence of DNA damage. RNA modifications dynamically coordinate transcript stability, RNA processing, translation, alternative splicing, R-loop homeostasis, DNA: RNA hybrid dynamics, repair factor recruitment, metabolic adaptation, replication stress tolerance, and cell-cycle checkpoint activation, thereby reshaping cellular responses to genotoxic stress. Importantly, accumulating evidence suggests that RNA modifications rarely function through isolated signaling pathways. Instead, distinct epitranscriptomic marks converge on shared biological processes that collectively determine genome stability, DNA repair capacity, and therapeutic responsiveness. In this Review, we provide a comprehensive overview of how RNA modifications remodel the DDR throughout cancer evolution, with particular emphasis on cancer type-specific mechanisms rather than conventional modification-based classification. We discuss recent advances across multiple malignancies, including lung cancer, breast cancer, ovarian cancer, hepatocellular carcinoma, glioblastoma, bladder cancer, colorectal cancer, pancreatic cancer, osteosarcoma, and other solid tumors. Furthermore, we critically evaluate the current evidence supporting individual regulatory mechanisms, distinguish well-established causal pathways from observations that remain largely correlative or context-dependent, and highlight unresolved controversies that continue to limit clinical translation. Finally, we discuss the major conceptual and technical challenges facing the field and propose future directions for integrating the RNA modification–DDR axis into precision oncology.