期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 8, 页码 1928-1933出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1615133114
关键词
centromere; genome integrity; alpha-satellite repeats; cancer; CO-FISH
资金
- American-Italian Cancer Foundation
- Women in Science Rockefeller fellowships
- Tri-Institutional Stem Cell Initiative [2013-049]
Centromeres are highly specialized chromatin domains that enable chromosome segregation and orchestrate faithful cell division. Human centromeres are composed of tandem arrays of a-satellite DNA, which spans up to several megabases. Little is known about the mechanisms that maintain integrity of the long arrays of a-satellite DNA repeats. Here, we monitored centromeric repeat stability in human cells using chromosome-orientation fluorescent in situ hybridization (CO-FISH). This assay detected aberrant centromeric CO-FISH patterns consistent with sister chromatid exchange at the frequency of 5% in primary tissue culture cells, whereas higher levels were seen in several cancer cell lines and during replicative senescence. To understand the mechanism(s) that maintains centromere integrity, we examined the contribution of the centromere-specific histone variant CENP-A and members of the constitutive centromere-associated network (CCAN), CENP-C, CENP-T, and CENP-W. Depletion of CENP-A and CCAN proteins led to an increase in centromere aberrations, whereas enhancing chromosome missegregation by alternative methods did not, suggesting that CENP-A and CCAN proteins help maintain centromere integrity independently of their role in chromosome segregation. Furthermore, superresolution imaging of centromeric CO-FISH using structured illumination microscopy implied that CENP-A protects a-satellite repeats from extensive rearrangements. Our study points toward the presence of a centromere-specificmechanism that actively maintains a-satellite repeat integrity during human cell proliferation.
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