Starting from a single fertilized egg, trillions of rounds of DNA replication must occur during development to generate the vast array of cells that comprise the human body. Remarkably, with an estimated 330 billion cells replaced each day, the total length of DNA synthesized daily in an adult surpasses the distance from the Earth to the Sun. This demanding task imposes a formidable challenge to the fidelity of DNA replication. The stability of the genome in the cell is further threatened by numerous factors that impede replication fork progression. Environmental insults, such as radiation and genotoxic chemicals, can damage the DNA template and stall replication [1], [2], [3]. Equally important are intrinsic sources of stress that disrupt fork dynamics, including metabolic byproducts like reactive oxygen species and aldehydes, collisions between the replication and transcription machinery, repetitive DNA elements such as telomeres, secondary structure-prone sequences like hairpins and G-quadruplexes, DNA-RNA hybrids in R-loops, misincorporated ribonucleotides, and insufficient levels of DNA precursors [1], [4], [5]. To cope with these challenges, cells have evolved a network of surveillance and repair mechanisms that detect replication stress, stabilize and protect stalled forks, resolve structural impediments, and facilitate fork restart to complete replication. These pathways are crucial for maintaining genome stability and ensuring proper cellular function. Deficiencies in these systems can give rise to a broad spectrum of diseases, including cancer, premature aging, developmental disorders, and neurological conditions [6], [7], [8].

In this perspective, we highlight recent advances in understanding fork protection under replication stress, with a particular focus on a newly identified Ca2+-dependent signaling pathway. For comprehensive coverage of other fork protection and recovery mechanisms, readers are directed to several excellent reviews on the topic [9], [10], [11], [12], [13], [14], [15].