Reciprocal control of genome instability and RNA processing in cancer: Mechanisms and therapeutic opportunities

Genomic instability and dysregulated RNA processing are each recognized as core hallmarks of cancer, but accumulating evidence indicates that they are mechanistically intertwined rather than independent features. Chromosomal instability, mismatch-repair deficiency, and homologous recombination deficiency can reshape RNA splicing, 3′ end formation, and RNA surveillance through changes in gene dosage, DNA damage signaling, and alterations in regulatory elements. Conversely, aberrant splicing, polyadenylation, and RNA modifications can impair DNA repair, perturb mitotic control, and promote replication stress, thereby reinforcing genomic instability. This bidirectional circuit drives clinically relevant phenotypes, including therapeutic resistance, immune modulation, and emergent vulnerabilities that are not captured by DNA-centric biomarkers alone. Here, we present a unified framework for the genome instability–RNA processing axis and its direct clinical implications for cancer diagnosis, treatment stratification, and therapeutic exploitation, highlighting the most actionable mechanistic interfaces and discussing how integrated DNA-RNA biomarkers and rational combination strategies could extend precision oncology beyond static genomic lesions.