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Redox-sensitive alteration of replisome architecture safeguards genome integrity

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Science  10 Nov 2017:
Vol. 358, Issue 6364, pp. 797-802
DOI: 10.1126/science.aao3172

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Metabolic regulation of genome stability

Cells respond to metabolic fluctuations by adjusting the speed of DNA replication as a safeguard for genome stability. Somyajit et al. elucidate the cellular mechanisms that align replication fork dynamics with metabolic pathways (see the Perspective by Gómez-González and Aguilera). The elevation of reactive oxygen species (ROS) levels under metabolic stress dissociates a replication accelerator from the replisome and leads to replication slowdown, thus preventing replication stress. Studying this genome surveillance mechanism in cancer cells with elevated ROS levels and increased replication adaptability may provide opportunities to specifically target tumors.

Science, this issue p. 797; see also p. 722

Abstract

DNA replication requires coordination between replication fork progression and deoxynucleotide triphosphate (dNTP)–generating metabolic pathways. We find that perturbation of ribonucleotide reductase (RNR) in humans elevates reactive oxygen species (ROS) that are detected by peroxiredoxin 2 (PRDX2). In the oligomeric state, PRDX2 forms a replisome-associated ROS sensor, which binds the fork accelerator TIMELESS when exposed to low levels of ROS. Elevated ROS levels generated by RNR attenuation disrupt oligomerized PRDX2 to smaller subunits, whose dissociation from chromatin enforces the displacement of TIMELESS from the replisome. This process instantly slows replication fork progression, which mitigates pathological consequences of replication stress. Thus, redox signaling couples fluctuations of dNTP biogenesis with replisome activity to reduce stress during genome duplication. We propose that cancer cells exploit this pathway to increase their adaptability to adverse metabolic conditions.

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