Redox-sensitive alteration of replisome architecture safeguards genome integrity
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Redox-sensitive alteration of replisome architecture safeguards genome integrity. / Somyajit, Kumar; Gupta, Rajat; Sedlackova, Hana; Neelsen, Kai John; Ochs, Fena; Rask, Maj-Britt; Choudhary, Chunaram; Lukas, Jiri.
In: Science, Vol. 358, No. 6364, 10.11.2017, p. 797-802.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Redox-sensitive alteration of replisome architecture safeguards genome integrity
AU - Somyajit, Kumar
AU - Gupta, Rajat
AU - Sedlackova, Hana
AU - Neelsen, Kai John
AU - Ochs, Fena
AU - Rask, Maj-Britt
AU - Choudhary, Chunaram
AU - Lukas, Jiri
N1 - Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
PY - 2017/11/10
Y1 - 2017/11/10
N2 - 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.
AB - 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.
U2 - 10.1126/science.aao3172
DO - 10.1126/science.aao3172
M3 - Journal article
C2 - 29123070
VL - 358
SP - 797
EP - 802
JO - Science
JF - Science
SN - 0036-8075
IS - 6364
ER -
ID: 186152687