Abstract
The centromere-specific histone H3 variant, CENP-A, is overexpressed in particular aggressive cancer cells, where it can be mislocalized ectopically in the form of heterotypic nucleosomes containing H3.3. In the present study, we report the crystal structure of the heterotypic CENP-A/H3.3 particle and reveal its “hybrid structure”, in which the physical characteristics of CENP-A and H3.3 are conserved independently within the same particle. The CENP-A/H3.3 nucleosome forms an unexpectedly stable structure as compared to the CENP-A nucleosome, and allows the binding of the essential centromeric protein, CENP-C, which is ectopically mislocalized in the chromosomes of CENP-A overexpressing cells.
Highlights
The centromere-specific histone H3 variant, CENP-A, is overexpressed in particular aggressive cancer cells, where it can be mislocalized ectopically in the form of heterotypic nucleosomes containing H3.3
The CENP-A/H3.3 nucleosome retains the ability to bind to the essential centromeric protein, CENP-C, whose ectopic localization may be harmful for the proper regulation of cell division and chromosome integrity
Human histones H2A, H2B, H3.3, H4, and CENP-A were prepared as described previously[26,27], and histone H3.3 was prepared as a His6-SUMO tagged protein expressed in bacteria (Supplementary Fig. 1a)
Summary
The centromere-specific histone H3 variant, CENP-A, is overexpressed in particular aggressive cancer cells, where it can be mislocalized ectopically in the form of heterotypic nucleosomes containing H3.3. In human cells, CENP-A overexpression can lead to its ectopic localization to chromosome regions with active histone turnover, as shown in cancer cell lines[19,24]. At these ectopic loci, CENP-A forms heterotypic nucleosomes, containing one each of the histone H3 variants, CENP-A and histone H3.3, within a single nucleosome[24]. The CENP-A/H3.3 nucleosome retains the ability to bind to the essential centromeric protein, CENP-C, whose ectopic localization may be harmful for the proper regulation of cell division and chromosome integrity
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