title: Centromere-independent accumulation of cohesin at ectopic heterochromatin sites induces chromosome stretching during anaphase.
abstract: Pericentric heterochromatin, while often considered as "junk" DNA, plays important functions in chromosome biology. It contributes to sister chromatid cohesion, a process mediated by the cohesin complex that ensures proper genome segregation during nuclear division. Long stretches of heterochromatin are almost exclusively placed at centromere-proximal regions but it remains unclear if there is functional (or mechanistic) importance in linking the sites of sister chromatid cohesion to the chromosomal regions that mediate spindle attachment (the centromere). Using engineered chromosomes in Drosophila melanogaster, we demonstrate that cohesin enrichment is dictated by the presence of heterochromatin rather than centromere proximity. This preferential accumulation is caused by an enrichment of the cohesin-loading factor (Nipped-B/NIPBL/Scc2) at dense heterochromatic regions. As a result, chromosome translocations containing ectopic pericentric heterochromatin embedded in euchromatin display additional cohesin-dependent constrictions. These ectopic cohesion sites, placed away from the centromere, disjoin abnormally during anaphase and chromosomes exhibit a significant increase in length during anaphase (termed chromatin stretching). These results provide evidence that long stretches of heterochromatin distant from the centromere, as often found in many cancers, are sufficient to induce abnormal accumulation of cohesin at these sites and thereby compromise the fidelity of chromosome segregation.
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal; Department of Biochemistry, University of Oxford, United Kingdom.
authors.forename: Raquel A
authors.initials: RA
authors.lastname: Oliveira
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, California.
authors.forename: Shaila
authors.initials: S
authors.lastname: Kotadia
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Tavares
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Mihailo
authors.initials: M
authors.lastname: Mirkovic
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, California.
authors.forename: Katherine
authors.initials: K
authors.lastname: Bowlin
authors.affiliation: Department of Biochemistry, University of Oxford, United Kingdom.
authors.forename: Christian S
authors.initials: CS
authors.lastname: Eichinger
authors.affiliation: Department of Biochemistry, University of Oxford, United Kingdom.
authors.forename: Kim
authors.initials: K
authors.lastname: Nasmyth
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, California.
authors.forename: William
authors.initials: W
authors.lastname: Sullivan
mesh_terms: D000705:Anaphase; D000818:Animals; D030801:Animals, Genetically Modified; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002503:Centromere; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D059006:Chromosomes, Insect / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster; D006570:Heterochromatin / Q000378:metabolism*; D008297:Male; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D006570:Heterochromatin; D000097722:Cohesins; C119839:nipped-B protein, Drosophila