title: Cohesin-SA1 deficiency drives aneuploidy and tumourigenesis in mice due to impaired replication of telomeres.
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.
authors.affiliation: Chromosome Dynamics Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Remeseiro
authors.forename: Ana
authors.initials: A
authors.lastname: Cuadrado
authors.forename: María
authors.initials: M
authors.lastname: Carretero
authors.forename: Paula
authors.initials: P
authors.lastname: Martínez
authors.forename: William C
authors.initials: WC
authors.lastname: Drosopoulos
authors.forename: Marta
authors.initials: M
authors.lastname: Cañamero
authors.forename: Carl L
authors.initials: CL
authors.lastname: Schildkraut
authors.forename: María A
authors.initials: MA
authors.lastname: Blasco
authors.forename: Ana
authors.initials: A
authors.lastname: Losada
mesh_terms: D000782:Aneuploidy; D000818:Animals; D002273:Carcinogens; D018797:Cell Cycle Proteins / Q000172:deficiency* / Q000235:genetics; D002460:Cell Line; D002842:Chromatids / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000172:deficiency* / Q000235:genetics; D020090:Chromosome Segregation; D004052:Diethylnitrosamine; D005354:Fibrosarcoma / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D008297:Male; D008748:Methylcholanthrene; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D021122:Protein Subunits / Q000172:deficiency* / Q000235:genetics; D012854:Sister Chromatid Exchange; D016615:Telomere / Q000378:metabolism*; D000097722:Cohesins
chemical_list: D002273:Carcinogens; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004052:Diethylnitrosamine; D008748:Methylcholanthrene; D021122:Protein Subunits; D000097722:Cohesins