Redox-sensitive alteration of replisome architecture safeguards genome integrity

Kumar Somyajit, Rajat Gupta, Hana Sedlackova, Kai John Neelsen, Fena Ochs, Maj-Britt Rask, Chunaram Choudhary, Jiri Lukas

Research output: Contribution to journalJournal articleResearchpeer-review

120 Citations (Scopus)
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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.

Original languageEnglish
JournalScience
Volume358
Issue number6364
Pages (from-to)797-802
Number of pages6
ISSN0036-8075
DOIs
Publication statusPublished - 10 Nov 2017

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