The inner centromere-shugoshin network prevents chromosomal instability.

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.