Homology-directed repair protects the replicating genome from metabolic assaults
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Homology-directed repair protects the replicating genome from metabolic assaults. / Somyajit, Kumar; Spies, Julian; Coscia, Fabian; Kirik, Ufuk; Rask, Maj-Britt; Lee, Ji-Hoon; Neelsen, Kai John; Mund, Andreas; Jensen, Lars Juhl; Paull, Tanya T.; Mann, Matthias; Lukas, Jiri.
In: Developmental Cell, Vol. 56, No. 4, 2021, p. 461-477.e7.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Homology-directed repair protects the replicating genome from metabolic assaults
AU - Somyajit, Kumar
AU - Spies, Julian
AU - Coscia, Fabian
AU - Kirik, Ufuk
AU - Rask, Maj-Britt
AU - Lee, Ji-Hoon
AU - Neelsen, Kai John
AU - Mund, Andreas
AU - Jensen, Lars Juhl
AU - Paull, Tanya T.
AU - Mann, Matthias
AU - Lukas, Jiri
N1 - Copyright © 2021 Elsevier Inc. All rights reserved.
PY - 2021
Y1 - 2021
N2 - Homology-directed repair (HDR) safeguards DNA integrity under various forms of stress, but how HDR protects replicating genomes under extensive metabolic alterations remains unclear. Here, we report that besides stalling replication forks, inhibition of ribonucleotide reductase (RNR) triggers metabolic imbalance manifested by the accumulation of increased reactive oxygen species (ROS) in cell nuclei. This leads to a redox-sensitive activation of the ATM kinase followed by phosphorylation of the MRE11 nuclease, which in HDR-deficient settings degrades stalled replication forks. Intriguingly, nascent DNA degradation by the ROS-ATM-MRE11 cascade is also triggered by hypoxia, which elevates signaling-competent ROS and attenuates functional HDR without arresting replication forks. Under these conditions, MRE11 degrades daughter-strand DNA gaps, which accumulate behind active replisomes and attract error-prone DNA polymerases to escalate mutation rates. Thus, HDR safeguards replicating genomes against metabolic assaults by restraining mutagenic repair at aberrantly processed nascent DNA. These findings have implications for cancer evolution and tumor therapy.
AB - Homology-directed repair (HDR) safeguards DNA integrity under various forms of stress, but how HDR protects replicating genomes under extensive metabolic alterations remains unclear. Here, we report that besides stalling replication forks, inhibition of ribonucleotide reductase (RNR) triggers metabolic imbalance manifested by the accumulation of increased reactive oxygen species (ROS) in cell nuclei. This leads to a redox-sensitive activation of the ATM kinase followed by phosphorylation of the MRE11 nuclease, which in HDR-deficient settings degrades stalled replication forks. Intriguingly, nascent DNA degradation by the ROS-ATM-MRE11 cascade is also triggered by hypoxia, which elevates signaling-competent ROS and attenuates functional HDR without arresting replication forks. Under these conditions, MRE11 degrades daughter-strand DNA gaps, which accumulate behind active replisomes and attract error-prone DNA polymerases to escalate mutation rates. Thus, HDR safeguards replicating genomes against metabolic assaults by restraining mutagenic repair at aberrantly processed nascent DNA. These findings have implications for cancer evolution and tumor therapy.
U2 - 10.1016/j.devcel.2021.01.011
DO - 10.1016/j.devcel.2021.01.011
M3 - Journal article
C2 - 33621493
VL - 56
SP - 461-477.e7
JO - Developmental Cell
JF - Developmental Cell
SN - 1534-5807
IS - 4
ER -
ID: 257925670