DNA Sequence-Specific Binding of CENP-B Enhances the Fidelity of Human Centromere Function

Daniele Fachinetti, Joo Seok Han, Moira A. McMahon, Peter Ly, Amira Abdullah, Alex J. Wong, Don W. Cleveland

Research output: Contribution to journalArticle

86 Scopus citations

Abstract

Human centromeres are specified by a stably inherited epigenetic mark that maintains centromere position and function through a two-step mechanism relying on self-templating centromeric chromatin assembled with the histone H3 variant CENP-A, followed by CENP-A-dependent nucleation of kinetochore assembly. Nevertheless, natural human centromeres are positioned within specific megabase chromosomal regions containing α-satellite DNA repeats, which contain binding sites for the DNA sequence-specific binding protein CENP-B. We now demonstrate that CENP-B directly binds both CENP-A's amino-terminal tail and CENP-C, a key nucleator of kinetochore assembly. DNA sequence-dependent binding of CENP-B within α-satellite repeats is required to stabilize optimal centromeric levels of CENP-C. Chromosomes bearing centromeres without bound CENP-B, including the human Y chromosome, are shown to mis-segregate in cells at rates several-fold higher than chromosomes withCENP-B-containing centromeres. These data demonstrate a DNA sequence-specific enhancement by CENP-B of the fidelity of epigenetically defined human centromere function.

Original languageEnglish (US)
Pages (from-to)314-327
Number of pages14
JournalDevelopmental Cell
Volume33
Issue number3
DOIs
StatePublished - May 4 2015
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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    Fachinetti, D., Han, J. S., McMahon, M. A., Ly, P., Abdullah, A., Wong, A. J., & Cleveland, D. W. (2015). DNA Sequence-Specific Binding of CENP-B Enhances the Fidelity of Human Centromere Function. Developmental Cell, 33(3), 314-327. https://doi.org/10.1016/j.devcel.2015.03.020