The inner centromere–shugoshin network prevents chromosomal instability

• Published in: Science (American Association for the Advancement of Science) Vol. 349; no. 6253; pp. 1237 - 1240
• Main Authors: Tanno, Yuji, Susumu, Hiroaki, Kawamura, Miyuki, Sugimura, Haruhiko, Honda, Takashi, Watanabe, Yoshinori
• Format: Journal Article
• Language: English
• Published: Washington American Association for the Advancement of Science 11.09.2015; The American Association for the Advancement of Science
• Subjects: Cancer; Cell division; Chromosomes; Cohesion; Histones; Instability; Lysine; Molecular biology; Networks; Stability; Tumorigenesis
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aaa2655

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.