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

Silvia Remeseiro, Ana Cuadrado, María Carretero, Paula Mart́nez, William C. Drosopoulos, Marta Cañamero, Carl L. Schildkraut, Maŕa A. Blasco, Ana Losada

Research output: Contribution to journalArticle

101 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2076-2089
Number of pages14
JournalEMBO Journal
Volume31
Issue number9
DOIs
StatePublished - May 2 2012

Keywords

  • cancer
  • chromosome segregation
  • cohesion
  • embryonic development
  • mouse model

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Remeseiro, S., Cuadrado, A., Carretero, M., Mart́nez, P., Drosopoulos, W. C., Cañamero, M., Schildkraut, C. L., Blasco, M. A., & Losada, A. (2012). Cohesin-SA1 deficiency drives aneuploidy and tumourigenesis in mice due to impaired replication of telomeres. EMBO Journal, 31(9), 2076-2089. https://doi.org/10.1038/emboj.2012.11