Journal
SCIENCE
Volume 349, Issue 6253, Pages 1237-1240Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aaa2655
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Funding
- JSPS KAKENHI [24770180, 26440093]
- JSPS
- MEXT KAKENHI grants [S-001, 25000014]
- Grants-in-Aid for Scientific Research [26440093, 25000014, 24770180] Funding Source: KAKEN
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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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