Cohesin-SA1 deficiency drives aneuploidy and tumourigenesis in mice due to impaired replication of telomeres

EMBO J. 2012 May 2;31(9):2076-89. doi: 10.1038/emboj.2012.11. Epub 2012 Mar 13.

Abstract

Cohesin is a protein complex originally identified for its role in sister chromatid cohesion, although increasing evidence portrays it also as a major organizer of interphase chromatin. Vertebrate cohesin consists of Smc1, Smc3, Rad21/Scc1 and either stromal antigen 1 (SA1) or SA2. To explore the functional specificity of these two versions of cohesin and their relevance for embryonic development and cancer, we generated a mouse model deficient for SA1. Complete ablation of SA1 results in embryonic lethality, while heterozygous animals have shorter lifespan and earlier onset of tumourigenesis. SA1-null mouse embryonic fibroblasts show decreased proliferation and increased aneuploidy as a result of chromosome segregation defects. These defects are not caused by impaired centromeric cohesion, which depends on cohesin-SA2. Instead, they arise from defective telomere replication, which requires cohesion mediated specifically by cohesin-SA1. We propose a novel mechanism for aneuploidy generation that involves impaired telomere replication upon loss of cohesin-SA1, with clear implications in tumourigenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aneuploidy*
  • Animals
  • Carcinogens
  • Cell Cycle Proteins / deficiency*
  • Cell Cycle Proteins / genetics
  • Cell Line
  • Chromatids / metabolism
  • Chromosomal Proteins, Non-Histone / deficiency*
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosome Segregation
  • Diethylnitrosamine
  • Fibrosarcoma / chemically induced
  • Fibrosarcoma / genetics
  • Fibrosarcoma / pathology
  • Liver Neoplasms / chemically induced
  • Liver Neoplasms / genetics
  • Liver Neoplasms / pathology
  • Male
  • Methylcholanthrene
  • Mice
  • Mice, Knockout
  • Neoplasms, Experimental / chemically induced
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / pathology
  • Protein Subunits / deficiency*
  • Protein Subunits / genetics
  • Sister Chromatid Exchange
  • Telomere / metabolism*

Substances

  • Carcinogens
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • Protein Subunits
  • cohesins
  • Diethylnitrosamine
  • Methylcholanthrene