Termination of DNA replication forks: "Breaking up is hard to do"

Nucleus. 2015;6(3):187-96. doi: 10.1080/19491034.2015.1035843. Epub 2015 Apr 2.

Abstract

To ensure duplication of the entire genome, eukaryotic DNA replication initiates from thousands of replication origins. The replication forks move through the chromatin until they encounter forks from neighboring origins. During replication fork termination forks converge, the replisomes disassemble and topoisomerase II resolves the daughter DNA molecules. If not resolved efficiently, terminating forks result in genomic instability through the formation of pathogenic structures. Our recent findings shed light onto the mechanism of replisome disassembly upon replication fork termination. We have shown that termination-specific polyubiquitylation of the replicative helicase component - Mcm7, leads to dissolution of the active helicase in a process dependent on the p97/VCP/Cdc48 segregase. The inhibition of terminating helicase disassembly resulted in a replication termination defect. In this extended view we present hypothetical models of replication fork termination and discuss remaining and emerging questions in the DNA replication termination field.

Keywords: CMG, Cdc45, Mcm2–7, GINS complex; CRL, cullin-RING ligase; D loop, displacement loop; DDR, DNA damage response; DNA replication; DSB, double strand break; DUB, deubiquitylating enzyme; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum associated protein degradation; GINS, Go-Ichi-Ni-San, complex made of Sld5, Psf1, Psf2, Psf3; ICL, intra-strand crosslink; MCM, Minichromosome maintenance; Mcm2–7; OriC, chromosomal replication origin; R loop, RNA:DNA hybrid; RING, really interesting gene; RPC, Replisome Progression Complex; Ter, termination site; Tus-Ter, terminus utilisation substance - termination; Xenopus; p97 segregase; replication termination; replicative helicase; replisome; ubiquitin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism*
  • Animals
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Chromatin / chemistry
  • Chromatin / metabolism*
  • DNA / genetics
  • DNA / metabolism
  • DNA Polymerase I / genetics
  • DNA Polymerase I / metabolism
  • DNA Polymerase II / genetics
  • DNA Polymerase II / metabolism
  • DNA Polymerase III / genetics
  • DNA Polymerase III / metabolism
  • DNA Replication*
  • DNA Topoisomerases, Type II / genetics
  • DNA Topoisomerases, Type II / metabolism*
  • Gene Expression Regulation
  • Genomic Instability
  • Humans
  • Minichromosome Maintenance Proteins / genetics
  • Minichromosome Maintenance Proteins / metabolism*
  • Polyubiquitin / genetics
  • Polyubiquitin / metabolism
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins
  • Signal Transduction
  • Ubiquitination
  • Valosin Containing Protein
  • Xenopus laevis / genetics
  • Xenopus laevis / metabolism

Substances

  • Cell Cycle Proteins
  • Chromatin
  • Saccharomyces cerevisiae Proteins
  • Polyubiquitin
  • DNA
  • DNA Polymerase I
  • DNA Polymerase II
  • DNA Polymerase III
  • Adenosine Triphosphatases
  • CDC48 protein, S cerevisiae
  • Minichromosome Maintenance Proteins
  • VCP protein, human
  • Valosin Containing Protein
  • DNA Topoisomerases, Type II