Homology-directed repair protects the replicating genome from metabolic assaults

Dev Cell. 2021 Feb 22;56(4):461-477.e7. doi: 10.1016/j.devcel.2021.01.011.


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.

Keywords: BRCA1/2; cancer evolution; genome instability; homology-directed repair; hypoxia; nascent DNA degradation; reactive oxygen species; replication stress; ribonucleotide reductase; translesion DNA synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • BRCA2 Protein / deficiency
  • BRCA2 Protein / metabolism
  • Cell Hypoxia
  • Cell Line, Tumor
  • DNA / metabolism
  • DNA Replication*
  • Genome, Human*
  • Humans
  • MRE11 Homologue Protein / metabolism
  • Metabolism*
  • Models, Biological
  • Mutation / genetics
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Polymerization
  • Reactive Oxygen Species / metabolism
  • Recombinational DNA Repair*
  • Signal Transduction


  • BRCA2 Protein
  • MRE11 protein, human
  • Reactive Oxygen Species
  • DNA
  • Ataxia Telangiectasia Mutated Proteins
  • MRE11 Homologue Protein