Abstract
In response to replication hindrances, DNA replication forks frequently stall and are remodelled into a four-way junction. In such a structure the annealed nascent strand is thought to resemble a DNA double-strand break and remodelled forks are vulnerable to nuclease attack by MRE11 and DNA2. Proteins that promote the recruitment, loading and stabilisation of RAD51 onto single-stranded DNA for homology search and strand exchange in homologous recombination (HR) repair and inter-strand cross-link repair also act to set up RAD51-mediated protection of nascent DNA at stalled replication forks. However, despite the similarities of these pathways, several lines of evidence indicate that fork protection is not simply analogous to the RAD51 loading step of HR. Protection of stalled forks not only requires separate functions of a number of recombination proteins, but also utilises nucleases important for the resection steps of HR in alternative ways. Here we discuss how fork protection arises and how its differences with HR give insights into the differing contexts of these two pathways.
Highlights
Protection of the reversed replication fork from untimely nuclease attack has emerged as a critical process for maintaining genome sta bility
Throughout this review, we examine the key factors involved in the closely linked processes of replication fork reversal and protection, and contrast their distinct functions in fork protection versus ho mologous recombination (HR)
Fork reversal is mediated by RAD51 [2,8,9,10], and the SNF2-family DNA translocases SMARCAL1, ZRANB3 and HLTF (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A Like 1, Zinc Finger RANBP2-Type Containing 3 and Helicase Like Transcription Factor, respectively) [11,12,13,14,15,16,17]
Summary
Protection of the reversed replication fork from untimely nuclease attack has emerged as a critical process for maintaining genome sta bility. Recent insights into both the mechanism and fundamental importance of replication fork protection have relied on a few key techniques (see Box 1 and Fig. 1), revealing significant overlap between factors involved in this process and homologous recombination (HR). Much of this work has underscored the relevance of replication fork protection to chemotherapeutic responses, demonstrating the potential clinical impact that a greater understanding of this process could hold. Throughout this review, we examine the key factors involved in the closely linked processes of replication fork reversal and protection, and contrast their distinct functions in fork protection versus HR
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