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Molecular and Cellular Biology, September 1999, p. 6130-6139, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Analysis of Primary Structural Determinants That Distinguish the Centromere-Specific Function of Histone Variant Cse4p from Histone H3

Kevin C. Keith,1,dagger Richard E. Baker,2 Yinhuai Chen,1 Kendra Harris,2 Sam Stoler,1 and Molly Fitzgerald-Hayes1,*

Department of Biochemistry and Molecular Biology, Program in Molecular and Cellular Biology, University of Massachusetts at Amherst, Amherst, Massachusetts 01003,1 and Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, Massachusetts 016552

Received 9 April 1999/Accepted 25 May 1999

Cse4p is a variant of histone H3 that has an essential role in chromosome segregation and centromere chromatin structure in budding yeast. Cse4p has a unique 135-amino-acid N terminus and a C-terminal histone-fold domain that is more than 60% identical to histone H3 and the mammalian centromere protein CENP-A. Cse4p and CENP-A have biochemical properties similar to H3 and probably replace H3 in centromere-specific nucleosomes in yeasts and mammals, respectively. In order to identify regions of Cse4p that distinguish it from H3 and confer centromere function, a systematic site-directed mutational analysis was performed. Nested deletions of the Cse4p N terminus showed that this region of the protein contains at least one essential domain. The C-terminal histone-fold domain of Cse4p was analyzed by changing Cse4p amino acids that differ between Cse4p and H3 to the analogous H3 residues. Extensive substitution of contiguous Cse4p residues with H3 counterparts resulted in cell lethality. However, all large lethal substitution alleles could be subdivided into smaller viable alleles, many of which caused elevated rates of mitotic chromosome loss. The results indicate that residues critical for wild-type Cse4p function and high-fidelity chromosome transmission are distributed across the entire histone-fold domain. Our findings are discussed in the context of the known structure of H3 within the nucleosome and compared with previous results reported for CENP-A.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, University of Massachusetts at Amherst, Lederle Graduate Research Ctr., Box 34505, Amherst, MA 01003. Phone: (413) 545-0235. Fax: (413) 545-3291. E-mail: mollyfh{at}biochem.umass.edu.

dagger Present address: University of Chicago, Chicago, IL 60637.

Molecular and Cellular Biology, September 1999, p. 6130-6139, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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