At a stalled DNA replication fork, how is replication restarted after DNA damage has been resolved?

2025年3月13日 · Replication forks stall when obstacles impede DNA polymerases, disrupting normal replication and requiring specialized mechanisms to prevent genome instability. Several factors contribute to fork stalling, including DNA lesions, …

Hydroxyurea-stalled replication forks become progressively inactivated and require two different RAD51-mediated pathways for restart and repair. Molecular Cell 37, 492–502 (2010).

It is now clear that replication forks stall frequently as a result of encounters between the replication machinery and template damage, slow-moving or paused transcription complexes, unrelieved positive superhelical tension, covalent protein-DNA complexes, and as a result of cellular stress responses.

2024年5月21日 · We have established an assay to identify genome wide hotspots where replication forks stall and pause, presenting that they showed in general increased genome instability, overlapped with replication fragile sites and with breakage sites of rearrangements found in cancer cells.

In this review, we focus on the recent progress in understanding the protection, processing, and remodeling of stalled replication forks in mammalian cells. During DNA replication, the replisome encounters many obstacles that pose a risk to precisely copying the genetic material.

2024年5月28日 · Fork reversal is a global response to many types of replication stress. Fork reversal indicates nascent DNA strands are reannealed together, accompanied by replication fork move backward (Zellweger et al., 2015).

2025年1月14日 · E3 ligase RAD18 was recruited at stalled replication forks in parallel to PCNA removal. Our results shed light on fork dynamics during nucleotide depletion and provide a valuable tool for interrogating the effects of replication stress-inducing anti-cancer agents.

Here, we review the mechanisms and major pathways rescuing stalled replication forks, with a focus on fork stabilization prevent-ing fork collapse.

In the laboratory, replication forks can be stalled by the action of hydroxyurea. Hydroxyurea depletes the cellular pools of dNTPs, which are needed by DNA polymerase for DNA synthesis. When dNTPs are unavailable, DNA synthesis slows down and ultimately stops completely.