Regulation of replication fork speed: Mechanisms and impact on genomic stability - PubMed (original) (raw)

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Regulation of replication fork speed: Mechanisms and impact on genomic stability

Joanna Maria Merchut-Maya et al. DNA Repair (Amst). 2019 Sep.

Abstract

Replication of DNA is a fundamental biological process that ensures precise duplication of the genome and thus safeguards inheritance. Any errors occurring during this process must be repaired before the cell divides, by activating the DNA damage response (DDR) machinery that detects and corrects the DNA lesions. Consistent with its significance, DNA replication is under stringent control, both spatial and temporal. Defined regions of the genome are replicated at specific times during S phase and the speed of replication fork progression is adjusted to fully replicate DNA in pace with the cell cycle. Insults that impair DNA replication cause replication stress (RS), which can lead to genomic instability and, potentially, to cell transformation. In this perspective, we review the current concept of replication stress, including the recent findings on the effects of accelerated fork speed and their impact on genomic (in)stability. We discuss in detail the Fork Speed Regulatory Network (FSRN), an integrated molecular machinery that regulates the velocity of DNA replication forks. Finally, we explore the potential for targeting FSRN components as an avenue to treat cancer.

Keywords: Cancer; DNA damage response; DNA replication; Fork speed regulatory network; Genome integrity; Replication forks.

Copyright © 2019 Elsevier B.V. All rights reserved.

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