PerspectiveCell Biology

The need to regulate replication fork speed

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Science  10 Nov 2017:
Vol. 358, Issue 6364, pp. 722-723
DOI: 10.1126/science.aaq0678

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The integrity of DNA is constantly threatened by the molecules that are endogenously generated by cell metabolism, the most common by-product being reactive oxygen species (ROS) (1). This is particularly relevant during DNA replication, as highlighted by the overrepresentation of replication-associated spontaneous mutations in cancer (2). In a constantly changing environment, cell survival requires a fine-tuned control of replication. Because DNA replication in eukaryotic cells initiates from multiple replication origins, it can be regulated at both the frequency of origin initiation and the rate of replication fork progression. The in vitro reconstitution of the eukaryotic replisome with purified proteins has recently boosted our knowledge of both processes in eukaryotes (3, 4). However, we still lack a full understanding of the mechanisms and implications of fork rate modulation in vivo. Notably, on page 797 of this issue, Somyajit et al. (5) show that the reduction of replication fork speed by low levels of ROS is a major mechanism to mitigate their negative impact on DNA replication and genome integrity, in a process that may be critical for tumor cell survival.