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The inner centromere–shugoshin network prevents chromosomal instability

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Science  11 Sep 2015:
Vol. 349, Issue 6253, pp. 1237-1240
DOI: 10.1126/science.aaa2655

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A misstep in the chromosomes' dance

The chromosomes of most cancer cells are unstable, suffering breaks and rearrangements. These aberrations perturb normal gene-regulatory programs and contribute to cancer progression. Tanno et al. studied several human cell lines that show chromosome instability. Homologous chromosomes did not pair very well with each other during cell division. These chromosomes had lost a specific chromatin covalent modification, methylation of histone H3 lysine 9, and/or the protein “glue” cohesin at the chromosomes' centromeres. Either of these losses interfered with the binding of the shugoshin 1 protein, which is required for proper chromosome pairing and segregation.

Science, this issue p. 1237

Abstract

Chromosomal instability (CIN) is a major trait of cancer cells and a potent driver of tumor progression. However, the molecular mechanisms underlying CIN still remain elusive. We found that a number of CIN+ cell lines have impairments in the integrity of the conserved inner centromere–shugoshin (ICS) network, which coordinates sister chromatid cohesion and kinetochore-microtubule attachment. These defects are caused mostly by the loss of histone H3 lysine 9 trimethylation at centromeres and sometimes by a reduction in chromatin-associated cohesin; both pathways separately sustain centromeric shugoshin stability. Artificial restoration of the ICS network suppresses chromosome segregation errors in a wide range of CIN+ cells, including RB- and BRCA1-deficient cells. Thus, dysfunction of the ICS network might be a key mechanism underlying CIN in human tumorigenesis.

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