The modulation of DNA replication dynamics has emerged as a key area of study in understanding genome stability and its perturbations in various physiological and pathological contexts. Replication fork rate is influenced by a variety of factors, including DNA repair pathways, origin firing, chromatin organization, transcription, and oncogenic signaling. This review highlights recent findings on the molecular mechanisms driving replication fork acceleration, focusing on scenarios such as PARP inhibition, oncogene activation, depletion of replication factors, and defects in Okazaki fragment processing. We discuss how reduced origin firing, R-loop resolution, and metabolic changes contribute to fork rate modulation, as well as the involvement of innate immune signaling, particularly through pathways such as cGAS-STING and ISG15. Special attention is given to consequences of accelerated replication forks for genome stability and their role in disease progression, particularly cancer. By unraveling the molecular mechanisms of fork acceleration, this Mini Review underscores its critical role in shaping genome integrity and cellular homeostasis, providing insights into future research directions and therapeutic strategies.

Department of Biochemistry and Molecular Biology University of Southern Denmark Odense Denmark

Laboratory of Genome Integrity Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacký University and University Hospital Olomouc Olomouc Czechia

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