A two-step mechanism for epigenetic specification of centromere identity and function
The basic determinant of chromosome inheritance, the centromere, is specified in many eukaryotes by an epigenetic mark. Using gene targeting in human cells and fission yeast, chromatin containing the centromere-specific histone H3 variant CENP-A is demonstrated to be the epigenetic mark that acts th...
|Published in:||Nature cell biology Vol. 15; no. 9; pp. 1056 - 1066|
|Main Authors:||Fachinetti, Daniele, Folco, H Diego, Nechemia-Arbely, Yael, Valente, Luis P, Nguyen, Kristen, Wong, Alex J, Zhu, Quan, Holland, Andrew J, Desai, Arshad, Jansen, Lars E T, Cleveland, Don W|
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The basic determinant of chromosome inheritance, the centromere, is specified in many eukaryotes by an epigenetic mark. Using gene targeting in human cells and fission yeast, chromatin containing the centromere-specific histone H3 variant CENP-A is demonstrated to be the epigenetic mark that acts through a two-step mechanism to identify, maintain and propagate centromere function indefinitely. Initially, centromere position is replicated and maintained by chromatin assembled with the centromere-targeting domain (CATD) of CENP-A substituted into H3. Subsequently, nucleation of kinetochore assembly onto CATD-containing chromatin is shown to require either the amino- or carboxy-terminal tail of CENP-A for recruitment of inner kinetochore proteins, including stabilizing CENP-B binding to human centromeres or direct recruitment of CENP-C, respectively.
Present address: Department of Molecular Biology & Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, 21205
Present address: Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
H.D.F. and A.D. designed and performed yeast experiments and contributed to manuscript writing. L.P.V. and L.E.T.J. performed FISH experiments. L.E.T.J. targeted the first CENP-A allele. D.F., Y.N., K.N., A.J.W., Q.Z., A.J.H. performed the experiments. D.F. analyzed the data. D.F. and D.W.C. conceived the experimental design and wrote the manuscript.