Posttranslational modifications of CENP-A: marks of distinction
Centromeres are specialized chromosome domain that serve as the site for kinetochore assembly and microtubule attachment during cell division, to ensure proper segregation of chromosomes. In higher eukaryotes, the identity of active centromeres is marked by the presence of CENP-A (centromeric protein-A), a histone H3 variant. CENP-A forms a centromere-specific nucleosome that acts as a foundation for centromere assembly and function. The posttranslational modification (PTM) of histone proteins is a major mechanism regulating the function of chromatin. While a few CENP-A site-specific modifications are shared with histone H3, the majority are specific to CENP-A-containing nucleosomes, indicating that modification of these residues contribute to centromere-specific function. CENP-A undergoes posttranslational modifications including phosphorylation, acetylation, methylation, and ubiquitylation. Work from many laboratories have uncovered the importance of these CENP-A modifications in its deposition at centromeres, protein stability, and recruitment of the CCAN (constitutive centromere-associated network). Here, we discuss the PTMs of CENP-A and their biological relevance.
KeywordsCENP-A Centromere Posttranslational modification Chromatin Mitosis Kinetochore
We thank Foltz lab members Ann Hogan and Ewelina Zasadzinska for their helpful discussion and inputs in the preparation of the manuscript.
D.R.F. was supported by NIH R01GM111907 and by a Zell Scholar award from the Robert H. Lurie Comprehensive Cancer Center.
- Boeckmann L, Takahashi Y, Au WC, Mishra PK, Choy JS, Dawson AR, Szeto MY, Waybright TJ, Heger C, McAndrew C et al (2013) Phosphorylation of centromeric histone H3 variant regulates chromosome segregation in Saccharomyces cerevisiae. Mol Biol Cell 24:2034–2044PubMedPubMedCentralCrossRefGoogle Scholar
- Cheeseman IM, Desai A (2008) Molecular architecture of the kinetochore-microtubule interface. Nat Rev. Mol Cell Biol 9:33–46Google Scholar
- Drinnenberg IA, de Young D, Henikoff S, Malik HS (2014) Recurrent loss of CenH3 is associated with independent transitions to holocentricity in insects. Elife 3.Google Scholar
- Earnshaw WC (2015) Discovering centromere proteins: from cold white hands to the A, B, C of CENPs. Nat Rev. Mol Cell Biol 16:443–449Google Scholar
- Hoffmann G, Samel-Pommerencke A, Weber J, Cuomo A, Bonaldi T, Ehrenhofer-Murray AE (2017) A role for CENP-A/Cse4 phosphorylation on serine 33 in deposition at the centromere. FEMS Yeast Res.Google Scholar
- Holland AJ, Cleveland DW (2009) Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nat Rev. Mol Cell Biol 10:478–487Google Scholar
- Niikura Y, Kitagawa R, Ogi H, Kitagawa K (2017b) SGT1-HSP90 complex is required for CENP-A deposition at centromeres. Cell Cycle, 1–12Google Scholar
- Ohkuni K, Takahashi Y, Fulp A, Lawrimore J, Au WC, Pasupala N, Levy-Myers R, Warren J, Strunnikov A, Baker RE, et al. (2016) SUMO-Targeted Ubiquitin Ligase (STUbL) Slx5 regulates proteolysis of centromeric histone H3 variant Cse4 and prevents its mislocalization to euchromatin. Mol Biol CellGoogle Scholar
- Ohkuni K, Levy-Myers R, Warren J, Au WC, Takahashi Y, Baker RE, Basrai MA (2018) N-terminal sumoylation of centromeric histone H3 variant Cse4 regulates its proteolysis to prevent mislocalization to non-centromeric chromatin. G3 (Bethesda)Google Scholar
- Pan D, Klare K, Petrovic A, Take A, Walstein K, Singh P, Rondelet A, Bird AW, Musacchio A (2017) CDK-regulated dimerization of M18BP1 on a Mis18 hexamer is necessary for CENP-A loading. Elife 6Google Scholar
- Takada M, Zhang W, Suzuki A, Kuroda TS, Yu Z, Inuzuka H, Gao D, Wan L, Zhuang M, Hu L, et al. (2017) FBW7 loss promotes chromosomal instability and tumorigenesis via cyclin E1/CDK2-mediated phosphorylation of CENP-A. Cancer ResGoogle Scholar
- Wang J, Liu X, Dou Z, Chen L, Jiang H, Fu C, Fu G, Liu D, Zhang J, Zhu T et al (2014) Mitotic regulator Mis18beta interacts with and specifies the centromeric assembly of molecular chaperone holliday junction recognition protein (HJURP). J Biol Chem 289:8326–8336PubMedPubMedCentralCrossRefGoogle Scholar