Double-strand DNA breaks recruit the centromeric histone CENP-A

Zeitlin, Samantha G.; Baker, N.; Chapados, Brian R.; Soutoglou, Evi; Wang, Jean Y. J.; Berns, Michael W.; Cleveland, Don W.

doi:10.1073/pnas.0908233106

Cited by 134 publications

(145 citation statements)

References 52 publications

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“…Consistent with this idea, a recent study in Xenopus egg extracts suggests that the human α-satellite repeats exhibit a relatively slow rate of replication fork progression (45). Alternatively, in line with CENP-A being implicated in the DNA damage response (46), presence of CENP-A on chromatin may directly facilitate the repair of lesions at centromeric repeats. It is also possible that chromatin compaction status may affect centromere integrity.…”

Section: Cenp-a-dependent Mechanism To Maintain Centromere Integritysupporting

confidence: 52%

Integrity of the human centromere DNA repeats is protected by CENP-A, CENP-C, and CENP-T

Giunta

Funabiki

2017

Proc. Natl. Acad. Sci. U.S.A.

105

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Centromeres are highly specialized chromatin domains that enable chromosome segregation and orchestrate faithful cell division. Human centromeres are composed of tandem arrays of α-satellite DNA, which spans up to several megabases. Little is known about the mechanisms that maintain integrity of the long arrays of α-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 α-satellite repeats from extensive rearrangements. Our study points toward the presence of a centromere-specific mechanism that actively maintains α-satellite repeat integrity during human cell proliferation.centromere | genome integrity | α-satellite repeats | cancer | CO-FISH

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Section: Cenp-a-dependent Mechanism To Maintain Centromere Integritysupporting

confidence: 52%

Integrity of the human centromere DNA repeats is protected by CENP-A, CENP-C, and CENP-T

Giunta

Funabiki

2017

Proc. Natl. Acad. Sci. U.S.A.

105

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“…3e,f), suggesting a (potentially dominant-negative) role for this isoform in the presence of DOXO. The observation that CENPA and CENPN but not other CENP proteins are recruited to DNA breaks in response to radiations 58 raises the possibility that the CENPN-pA13 isoform might prevent kinetochore assembly at DNA breaks. More generally, it is tempting to speculate that the recent evolution of ALEs in genes involved in DNA damage response and cell cycle provides an additional layer of gene expression regulation in complex processes and organisms.…”

Section: Discussionmentioning

confidence: 99%

A recently evolved class of alternative 3′-terminal exons involved in cell cycle regulation by topoisomerase inhibitors

et al. 2014

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Alternative 3 0 -terminal exons, which use intronic polyadenylation sites, are generally less conserved and expressed at lower levels than the last exon of genes. Here we discover a class of human genes, in which the last exon appeared recently during evolution, and the major gene product uses an alternative 3 0 -terminal exon corresponding to the ancestral last exon of the gene. This novel class of alternative 3 0 -terminal exons are downregulated on a large scale by doxorubicin, a cytostatic drug targeting topoisomerase II, and play a role in cell cycle regulation, including centromere-kinetochore assembly. The RNA-binding protein HuR/ ELAVL1 is a major regulator of this specific set of alternative 3 0 -terminal exons. HuR binding to the alternative 3 0 -terminal exon in the pre-messenger RNA promotes its splicing, and is reduced by topoisomerase inhibitors. These findings provide new insights into the evolution, function and molecular regulation of alternative 3 0 -terminal exons.

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“…However, other evidence demonstrates that CENP-A also binds to damaged DNA outside of centromeres. 46,47 CENP-A can be recruited throughout interphase by double-strand breaks. 47 This finding could reconcile prior disputes about timing.…”

Section: Point Of View Point Of Viewmentioning

confidence: 99%

“…46,47 CENP-A can be recruited throughout interphase by double-strand breaks. 47 This finding could reconcile prior disputes about timing. Importantly, common cell cycle synchronization methods employed in most timing studies can induce DNA damage and inhibit repair.…”

Section: Point Of View Point Of Viewmentioning

confidence: 99%