replicatiestress

Replicatiestress, commonly referred to as replication stress, is a cellular condition in which DNA replication is perturbed, causing slowing or stalling of replication forks during S phase. It can arise from obstacles to fork progression, collisions between replication and transcription machinery, DNA lesions, tightly bound protein complexes, oncogene activation, or nucleotide pool depletion.

When forks stall, exposed single-stranded DNA is coated by RPA, which helps activate the ATR kinase signaling pathway. ATR-ATRIP phosphorylates CHK1 and other targets, triggering cell cycle arrest, stabilization of the replication fork, and coordinated DNA damage responses. Fork protection mechanisms, including BRCA1/2 and FANCD2-FANCI, help prevent nucleolytic degradation of nascent DNA. Fork restart can occur through fork reversal and remodeling by factors such as SMARCAL1, ZRANB3, HLTF, and recombination-mediated restart involving RAD51.

If replication stress is not properly resolved, it can lead to DNA double-strand breaks, chromosomal rearrangements, and genome instability, contributing to aging and carcinogenesis. Replication stress is detectable by markers such as RPA foci, γ-H2AX, 53BP1, and activation of ATR/CHK1 signaling, and can be measured using assays like DNA fiber analysis and chromatin immunoprecipitation.

In cancer and other diseases, replication stress is both a driver of genomic instability and a therapeutic target. Tumors with BRCA1/2, FANCD2, or other homologous recombination defects are particularly sensitive to ATR inhibitors or treatments that exacerbate replication stress, illustrating a concept of synthetic lethality.