Chromosome missegregation and aneuploidy are commons characteristics of cancer. Centromeres are chromosomal loci that define the site of kinetochore formation and ensure faithful chromosome segregation during mitosis. Centromeric identity is epigenetically specified by the incorporation of CENP-A nucleosomes, independent of DNA sequence. Because of the chromatin nature of the centromere, the processes that govern CENP-A nucleosome assembly and nucleosome stability are essential to the maintenance of centromere specification. New CENP-A must be added to the centromere in a consistent and faithful manner during each cell cycle to maintain centromeric chromatin and centromere identity. New CENP-A nucleosomes are added to the centromere during G1 by the CENP-A specific chaperone HJURP, that is recruited to centromere by the Mis18 complex. Although unlike canonical histone H3, new CENP- A is not deposited during DNA replication; however, CENP-A nucleosomes are retained at the centromere during DNA replication to ensure the transmittance of the centromeric locus. The mechanism by which CENP-A nucleosomes are stably retained when chromatin is disassembled during DNA replication will be addressed in this application. Centromeres are located within the alpha-satellite DNA repeats in most individuals; however, several neocentromeres have been identified where centromere proteins relocate and function at non-centromeric sites. This application will address the ability of non-centromeric sites to acquire centromeric identity in order to understand the chromatin and genomic contributions to centromere function.
How the genome is faithfully segregated during each cell division is a fundamental question in biology, with implications for understanding the genesis of cancer. Chromosome segregation is controlled by the centromere, which is specified by a unique nucleosome containing the histone variant CENP-A. Our work will discover new mechanisms that explain how centromeric chromatin is assembled and maintained.
| Srivastava, Shashank; Zasadzi?ska, Ewelina; Foltz, Daniel R (2018) Posttranslational mechanisms controlling centromere function and assembly. Curr Opin Cell Biol 52:126-135 |
| Zasadzi?ska, Ewelina; Huang, Jiehuan; Bailey, Aaron O et al. (2018) Inheritance of CENP-A Nucleosomes during DNA Replication Requires HJURP. Dev Cell 47:348-362.e7 |
| Srivastava, Shashank; Foltz, Daniel R (2018) Posttranslational modifications of CENP-A: marks of distinction. Chromosoma 127:279-290 |
| Zasadzi?ska, Ewelina; Foltz, Daniel R (2017) Orchestrating the Specific Assembly of Centromeric Nucleosomes. Prog Mol Subcell Biol 56:165-192 |
| Sathyan, Kizhakke M; Fachinetti, Daniele; Foltz, Daniel R (2017) ?-amino trimethylation of CENP-A by NRMT is required for full recruitment of the centromere. Nat Commun 8:14678 |
| Barnhart-Dailey, Meghan C; Trivedi, Prasad; Stukenberg, P Todd et al. (2017) HJURP interaction with the condensin II complex during G1 promotes CENP-A deposition. Mol Biol Cell 28:54-64 |
| Shrestha, Roshan L; Ahn, Grace S; Staples, Mae I et al. (2017) Mislocalization of centromeric histone H3 variant CENP-A contributes to chromosomal instability (CIN) in human cells. Oncotarget 8:46781-46800 |
| Zasadzi?ska, Ewelina; Foltz, Daniel R (2016) Centromeres of a Different CAL-ibre. Dev Cell 37:105-6 |
| Nardi, Isaac K; Zasadzi?ska, Ewelina; Stellfox, Madison E et al. (2016) Licensing of Centromeric Chromatin Assembly through the Mis18?-Mis18? Heterotetramer. Mol Cell 61:774-787 |
| Bailey, Aaron O; Panchenko, Tanya; Shabanowitz, Jeffrey et al. (2016) Identification of the Post-translational Modifications Present in Centromeric Chromatin. Mol Cell Proteomics 15:918-31 |
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