Centromeres are maintained by fastening CENP-A to DNA and directing an arginine anchor-dependent nucleosome transition

Lucie Y. Guo, Praveen Kumar Allu, Levani Zandarashvili, Kara L. McKinley, Nikolina Sekulic, Jennine M. Dawicki-McKenna, Daniele Fachinetti, Glennis A. Logsdon, Ryan M. Jamiolkowski, Don W. Cleveland, Iain M. Cheeseman and Ben E. Black ()
Additional contact information
Lucie Y. Guo: Perelman School of Medicine, University of Pennsylvania
Praveen Kumar Allu: Perelman School of Medicine, University of Pennsylvania
Levani Zandarashvili: Perelman School of Medicine, University of Pennsylvania
Kara L. McKinley: Massachusetts Institute of Technology
Nikolina Sekulic: Perelman School of Medicine, University of Pennsylvania
Jennine M. Dawicki-McKenna: Perelman School of Medicine, University of Pennsylvania
Daniele Fachinetti: University of California, San Diego
Glennis A. Logsdon: Perelman School of Medicine, University of Pennsylvania
Ryan M. Jamiolkowski: Graduate Program in Bioengineering, University of Pennsylvania
Don W. Cleveland: University of California, San Diego
Iain M. Cheeseman: Massachusetts Institute of Technology
Ben E. Black: Perelman School of Medicine, University of Pennsylvania

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract Maintaining centromere identity relies upon the persistence of the epigenetic mark provided by the histone H3 variant, centromere protein A (CENP-A), but the molecular mechanisms that underlie its remarkable stability remain unclear. Here, we define the contributions of each of the three candidate CENP-A nucleosome-binding domains (two on CENP-C and one on CENP-N) to CENP-A stability using gene replacement and rapid protein degradation. Surprisingly, the most conserved domain, the CENP-C motif, is dispensable. Instead, the stability is conferred by the unfolded central domain of CENP-C and the folded N-terminal domain of CENP-N that becomes rigidified 1,000-fold upon crossbridging CENP-A and its adjacent nucleosomal DNA. Disrupting the ‘arginine anchor’ on CENP-C for the nucleosomal acidic patch disrupts the CENP-A nucleosome structural transition and removes CENP-A nucleosomes from centromeres. CENP-A nucleosome retention at centromeres requires a core centromeric nucleosome complex where CENP-C clamps down a stable nucleosome conformation and CENP-N fastens CENP-A to the DNA.

Date: 2017
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DOI: 10.1038/ncomms15775

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