Abstract
During genome replication, replication forks often encounter obstacles that impede their progression. Arrested forks are unstable structures that can give rise to collapse and rearrange if they are not properly processed and restarted. Replication fork reversal is a critical protective mechanism in higher eukaryotic cells in response to replication stress, in which forks reverse their direction to form a Holliday junction-like structure. The reversed replication forks are protected from nuclease degradation by DNA damage repair proteins, such as BRCA1, BRCA2, and RAD51. Some of these molecules work cooperatively, while others have unique functions. Once the stress is resolved, the replication forks can restart with the help of enzymes, including human RECQ1 helicase, but restart will not be considered here. Here, we review research on the key factors and mechanisms required for the remodeling and protection of stalled replication forks in mammalian cells.
Highlights
Faithful DNA replication during each cell cycle is essential for maintaining genome stability (Jeggo et al, 2016)
Proposed in 1976, replication fork reversal was long regarded as a pathological result of fork destabilization, but has been accepted as a DNA damage tolerance (DDT) based on recent observations of reversed fork structures in vivo and the identification of molecules involved in fork regression in vitro (Sakaguchi et al, 2009; Bermejo et al, 2011; Neelsen and Lopes, 2015; Berti et al, 2020a)
It actively slows down replication fork progression via multiple enzymes, such as the recombinase RAD51 and DNA translocase helicase-like transcription factor (HLTF), which
Summary
Faithful DNA replication during each cell cycle is essential for maintaining genome stability (Jeggo et al, 2016). The DNA replication process is frequently challenged by endogenous and exogenous sources of genotoxic stress, including DNA lesions, difficult to replicate sequences, and nucleotide depletion (Mehta and Haber, 2014; Kitao et al, 2018) These challenges, if not properly addressed, would cause genome instability, a hallmark of tumorigenesis (Jackson and Bartek, 2009; Ou and Schumacher, 2018). Emerging evidence suggests that replication fork reversal is indispensable for maintaining genome stability in higher eukaryotic cells. It actively slows down replication fork progression via multiple enzymes, such as the recombinase RAD51 and DNA translocase helicase-like transcription factor (HLTF), which. We hope that this review will provide comprehensive insight into replication fork reversal, thereby contributing to future therapies for diseases like cancers
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