Special Issue Information

During each cell division cycle, faithful genome duplication must overcome a broad spectrum of endogenous challenges - including transcription-replication conflicts, non-B DNA secondary structures, and imbalances in nucleotide pools - as well as exogenous sources of DNA damage. Inadequate sensing, signaling, or resolution of replication stress can lead to replication fork stalling or collapse, chromosomal rearrangements, and pervasive genomic instability, hallmark features of cancer, aging, and numerous inherited and acquired disorders.

The cellular response to replication stress is a tightly regulated and highly coordinated process. Checkpoint signaling pathways, replication fork protection mechanisms, and specialized DNA repair programs act in concert to stabilize perturbed replication forks, promote their restart, and ensure completion of genome duplication while preserving cellular fitness. In cancer, replication stress plays a dual role, functioning both as an early driver of tumorigenesis and as an exploitable therapeutic vulnerability. This paradigm is exemplified by the clinical success of PARP inhibitors and by emerging strategies targeting key replication stress response kinases, including ATR, CHK1, and WEE1. Beyond oncology, accumulating evidence links replication stress to age-associated genome instability, stem cell dysfunction, and degenerative diseases, underscoring its broad biological and clinical significance.

Despite substantial advances, fundamental questions remain unresolved. What are the dominant endogenous sources of replication stress across distinct cellular states, tissue types, and developmental stages? How is the replication stress response dynamically regulated and integrated with DNA repair pathway choice? Through what molecular mechanisms does unresolved replication stress give rise to catastrophic genome rearrangements, such as chromothripsis? Finally, how do replication stress response pathways differ between normal aging tissues and malignant cells, and can these differences be selectively exploited for therapeutic benefit?

This Special Issue invites original research articles and authoritative reviews that elucidate the molecular mechanisms, regulatory principles, and physiological or pathological consequences of replication stress and its associated responses. By integrating molecular, structural, cellular, and genomic perspectives, this collection aims to advance a unified understanding of genome maintenance and to stimulate the development of innovative strategies for the prevention and treatment of replication stress-driven diseases.

Contact Us