Homology-directed repair protects the replicating genome from metabolic assaults

Kumar Somyajit, Julian Spies, Fabian Coscia, Ufuk Kirik, Maj-Britt Rask, Ji-Hoon Lee, Kai John Neelsen, Andreas Mund, Lars Juhl Jensen, Tanya T. Paull, Matthias Mann, Jiri Lukas

Research output: Contribution to journalJournal articleResearchpeer-review

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.

Original languageEnglish
JournalDevelopmental Cell
Volume56
Issue number4
Pages (from-to)461-477.e7
ISSN1534-5807
DOIs
Publication statusPublished - 22. Feb 2021
Externally publishedYes

Keywords

  • BRCA1/2
  • cancer evolution
  • genome instability
  • homology-directed repair
  • hypoxia
  • nascent DNA degradation
  • reactive oxygen species
  • replication stress
  • ribonucleotide reductase
  • translesion DNA synthesis
  • DNA/metabolism
  • Humans
  • Neoplasms/genetics
  • Cell Hypoxia
  • MRE11 Homologue Protein/metabolism
  • Reactive Oxygen Species/metabolism
  • Recombinational DNA Repair
  • Signal Transduction
  • Mutation/genetics
  • Polymerization
  • DNA Replication
  • Metabolism
  • BRCA2 Protein/deficiency
  • Models, Biological
  • Ataxia Telangiectasia Mutated Proteins/metabolism
  • Cell Line, Tumor
  • Genome, Human

Fingerprint

Dive into the research topics of 'Homology-directed repair protects the replicating genome from metabolic assaults'. Together they form a unique fingerprint.

Cite this