Redox-sensitive alteration of replisome architecture safeguards genome integrity

• Published in: Science (American Association for the Advancement of Science) Vol. 358; no. 6364; pp. 797 - 802
• Main Authors: Somyajit, Kumar, Gupta, Rajat, Sedlackova, Hana, Neelsen, Kai John, Ochs, Fena, Rask, Maj-Britt, Choudhary, Chunaram, Lukas, Jiri
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 10.11.2017; The American Association for the Advancement of Science
• Subjects: Adaptability; Adaptation, Biological; Cancer; Cell Cycle Proteins - metabolism; Chromatin; Chromatin - metabolism; Deoxyribonucleic acid; Deoxyribonucleotides - metabolism; DNA; DNA biosynthesis; DNA damage; DNA Replication; Fluctuations; Genomes; Genomic Instability; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Metabolic Networks and Pathways; Metabolic pathways; Metabolism; Neoplasms - genetics; Oligomerization; Oxidation-Reduction; Peroxiredoxin; Peroxiredoxins - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; Reductase; Replication; Ribonucleotide reductase; Ribonucleotide Reductases - metabolism; Signal Transduction; Signaling; Stress; Stresses; Tumors
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aao3172

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.