Separase prevents genomic instability by controlling replication fork speed

Nucleic Acids Res. 2018 Jan 9;46(1):267-278. doi: 10.1093/nar/gkx1172.


Proper chromosome segregation is crucial for preserving genomic integrity, and errors in this process cause chromosome mis-segregation, which may contribute to cancer development. Sister chromatid separation is triggered by Separase, an evolutionary conserved protease that cleaves the cohesin complex, allowing the dissolution of sister chromatid cohesion. Here we provide evidence that Separase participates in genomic stability maintenance by controlling replication fork speed. We found that Separase interacted with the replication licensing factors MCM2-7, and genome-wide data showed that Separase co-localized with MCM complex and cohesin. Unexpectedly, the depletion of Separase increased the fork velocity about 1.5-fold and caused a strong acetylation of cohesin's SMC3 subunit and altered checkpoint response. Notably, Separase silencing triggered genomic instability in both HeLa and human primary fibroblast cells. Our results show a novel mechanism for fork progression mediated by Separase and thus the basis for genomic instability associated with tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cells, Cultured
  • Chromatids / genetics
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism
  • Chromosome Segregation
  • DNA / chemistry*
  • DNA / genetics
  • DNA / metabolism
  • DNA Replication*
  • Genomic Instability*
  • HeLa Cells
  • Humans
  • Minichromosome Maintenance Proteins / genetics
  • Minichromosome Maintenance Proteins / metabolism
  • Models, Genetic
  • Nucleic Acid Conformation*
  • Protein Binding
  • RNA Interference
  • Separase / genetics
  • Separase / metabolism*


  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • cohesins
  • DNA
  • Separase
  • Minichromosome Maintenance Proteins