Nucleases Acting at Stalled Forks: How to Reboot the Replication Program with a Few Shortcuts

Annu Rev Genet. 2017 Nov 27;51:477-499. doi: 10.1146/annurev-genet-120116-024745.


In a lifetime, a human being synthesizes approximately 2×1016 meters of DNA, a distance that corresponds to 130,000 times the distance between the Earth and the Sun. This daunting task is executed by thousands of replication forks, which progress along the chromosomes and frequently stall when they encounter DNA lesions, unusual DNA structures, RNA polymerases, or tightly-bound protein complexes. To complete DNA synthesis before the onset of mitosis, eukaryotic cells have evolved complex mechanisms to process and restart arrested forks through the coordinated action of multiple nucleases, topoisomerases, and helicases. In this review, we discuss recent advances in understanding the role and regulation of nucleases acting at stalled forks with a focus on the nucleolytic degradation of nascent DNA, a process commonly referred to as fork resection. We also discuss the effects of deregulated fork resection on genomic instability and on the unscheduled activation of the interferon response under replication stress conditions.

Keywords: exonucleases; genomic instability; homologous recombination; replication forks; replication stress; structure-specific nucleases.

Publication types

  • Review

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • DNA / genetics*
  • DNA / metabolism
  • DNA Breaks, Double-Stranded
  • DNA Cleavage
  • DNA Helicases / genetics*
  • DNA Helicases / metabolism
  • DNA Replication*
  • DNA Topoisomerases / genetics*
  • DNA Topoisomerases / metabolism
  • Endonucleases / genetics*
  • Endonucleases / metabolism
  • Genomic Instability
  • Humans
  • Interferon Type I / genetics
  • Interferon Type I / metabolism
  • Recombinational DNA Repair*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Schizosaccharomyces / genetics
  • Schizosaccharomyces / metabolism


  • Interferon Type I
  • DNA
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Endonucleases
  • DNA Helicases
  • DNA Topoisomerases