1. Homology-directed repair protects the replicating genome from metabolic assaults.
- Author
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Somyajit K, Spies J, Coscia F, Kirik U, Rask MB, Lee JH, Neelsen KJ, Mund A, Jensen LJ, Paull TT, Mann M, and Lukas J
- Subjects
- Ataxia Telangiectasia Mutated Proteins metabolism, BRCA2 Protein deficiency, BRCA2 Protein metabolism, Cell Hypoxia, Cell Line, Tumor, DNA metabolism, Humans, MRE11 Homologue Protein metabolism, Models, Biological, Mutation genetics, Neoplasms genetics, Neoplasms pathology, Polymerization, Reactive Oxygen Species metabolism, Signal Transduction, DNA Replication, Genome, Human, Metabolism, Recombinational DNA Repair
- Abstract
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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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