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The Centromere: Epigenetic Control of Chromosome Segregation During Mitosis

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The Centromere: Epigenetic Control of Chromosome Segregation During Mitosis Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press The Centromere: Epigenetic Control of Chromosome Segregation during Mitosis Frederick G. Westhorpe and Aaron F. Straight Department of Biochemistry, Stanford University Medical School, Stanford, California 94305 Correspondence: [email protected] A fundamental challenge for the survival of all organisms is maintaining the integrity of the genome in all cells. Cells must therefore segregate their replicated genome equally during each cell division. Eukaryotic organisms package their genome into a number of physically distinct chromosomes, which replicate during S phase and condense during prophase of mitosis to form paired sister chromatids. During mitosis, cells form a physical connection between each sister chromatid and microtubules of the mitotic spindle, which segregate one copy of each chromatid to each new daughter cell. The centromere is the DNA locus on each chromosome that creates the site of this connection. In this review, we present a brief history of centromere research and discuss our current knowledge of centromere establishment, maintenance, composition, structure, and function in mitosis. entromeres were first described by Walther of centromere biology, one universally accepted CFlemming (1882) in his pioneering charac- fact is that centromeres have an essential role terization of cell division. Flemming noticed in the segregation of chromosomes during mi- that the distinct threads of chromatin (later tosis. The centromere is a large chromatin- called chromosomes) each had one (and only containing protein complex that forms the as- one) site of primary constriction, where the total sembly site for the mitotic kinetochore, itself width of the chromosome appeared smaller a megadalton protein complex that binds spin- than the rest of that chromosome. We now rec- dle microtubules to segregate the chromatids ognize that Flemming was reporting the dis- during anaphase (Fig. 1). In addition to micro- tinct heterochromatin found specifically at cen- tubule attachment, kinetochores are also the tromeres. The term “chromatin” was originally site of mitotic checkpoint activation, which pre- proposed by Flemming as the chromosomes he vents anaphase onset in the presence of unat- was observing stain darkly when cells are treated tached kinetochores. Without the centromere, with aniline dyes. Since then, the definition of no kinetochore would form and cells could not chromatin has evolved, and now describes the segregate their chromosomes. Thus, the centro- histone proteins and associated proteins that mere is of crucial importance for chromosome package DNA. segregation and mitotic control. Although more than 130 years later we lack The mitotic centromere:kinetochore can be a detailed understanding of numerous aspects thought of as a single multiprotein complex. Editors: Mitsuhiro Yanagida, Anthony A. Hyman, and Jonathon Pines Additional Perspectives on Mitosis available at www.cshperspectives.org Copyright # 2014 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a015818 1 Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press F.G. Westhorpe and A.F. Straight A Chromosome Centromere Kinetochore Sister chromatids Prometaphase Metaphase Anaphase B Spindle microtubules Kinetochore proteins Centromere proteins (CCAN) Centromeric chromatin Figure 1. Introduction to centromere function and organization during mitosis. (A) Before and during the early stages of mitosis, centromeres (green circle) recruit kinetochore proteins (yellow discs). During prometaphase, the kinetochore forms the attachment sites for spindle microtubules (red rods). Once both kinetochores of all sister chromatid pairs are stably and correctly attached to microtubules, pulling forces exerted by microtubules (dashed arrows) cause migration of linked sister chromatids to the metaphase plate. At anaphase, sister chro- matid cohesion is dissolved and the centromere and kinetochore harness microtubule-dependent forces that pull each sister chromatid to opposite ends of the dividing cell. (B) Basic architecture of the centromere in mitosis. Centromeric chromatin consists of specialized nucleosomes containing the histone H3 variant centro- mere protein (CENP)-A. CENP-A recruits a network of centromere proteins (green) that are collectively known as the constitutive centromere associated network (CCAN). Kinetochore proteins (yellow), specifically recruited by the CCAN for mitosis, attach to spindle microtubules. However, kinetochore proteins localize to cen- network (CCAN) (Cheeseman and Desai 2008). tromeres before and during mitosis to enable This nomenclature system has provided some chromosome segregation, whereas centromere clarity in the field, but it should be noted that proteins (CENPs) persist throughout the cell many CCAN proteins dynamically associate and cycle. CENPs (listed in Fig. 3) are collectively dissociate from centromeres, and some func- called the constitutive centromere-associated tion in microtubule regulation during mitosis. 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a015818 Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press The Centromere Eukaryotic centromeres vary widely in their ing CENP-ACID-LacI fusion protein in cells con- complexity and structure, ranging from point taining chromosomally integrated Lac operator centromeres of budding yeast that generate a arrays, the localized CENP-ACID causes ectopic single microtubule-binding site, to holocentric kinetochore formation in Drosophila (Mendi- centromeres of nematodes that decorate the buro et al. 2011), and partial kinetochore for- entire chromosome, to regional centromeres of mation in humans (Gascoigne et al. 2011). Thus, vertebrates that provide a distinct attachment the presence of CENP-A in chromatin is the site for multiple microtubules. Despite this var- defining mark of centromeres. iation, the core function of the centromere, to form the kinetochore to bind microtubules so The Epigenetic Nature of Centromeres that chromosomes can be equally segregated in mitosis, is conserved. Thus, understanding the Understanding how CENP-A is assembled and molecular underpinnings of the centromere is maintained only at centromeres is central to un- fundamental to establishing how cells faithfully derstanding centromere and kinetochore func- maintain their genomes. tion. A simple model for how CENP-A is target- ed to the centromere is that specific centromeric DNA sequences dictate CENP-A nucleosome CENP-A: THE CENTROMERE-SPECIFIC position. This model appears true in the “point” HISTONE centromeres of some budding yeasts, including Eukaryotic DNA is assembled around histone Saccharomyces cerevisiae, which has a defined proteins into protein:DNA complexes known 125-bp centromeric DNA sequence consisting as nucleosomes. Nucleosomes throughout most of three centromere-DNA elements (CDEs) of a chromosome contain two copies of each that are necessary and sufficient for centromere histone protein H2A, H2B, H3, and H4, togeth- specification and kinetochore assembly (Clarke er forming an octameric complex with DNA and Carbon 1980; Fitzgerald-Hayes et al. 1982; (Fig. 2). Centromeres are unique from the rest Cottarel et al. 1989). A single CENP-ACse4 nu- of the chromosome in that they feature nucleo- cleosome is positioned at CDEII in a centromer- somes containing a histone H3 variant, called ic DNA sequence-dependent manner (Spencer CENP-A, in place of histone H3 (Fig. 2). CENP- and Hieter 1992; Stoler et al. 1995; Meluh et al. A was initially discovered as a human autoan- 1998; Furuyama and Biggins 2007), although tigen in CREST syndrome patients, and was recent evidence suggests multiple accessory subsequently shown to copurify with histones, CENP-ACse4 nucleosomes, proposed to not con- be present in purified nucleosomes, and be es- tribute to kinetochore formation, may exist at sential across eukaryotic model organisms, as centromeres (Coffman et al. 2011; Lawrimore et mutation or disruption of CENP-A causes a al. 2011; Haase et al. 2013). In contrast to bud- complete failure in centromere and kineto- ding yeast, fission yeast and higher eukaryotes, chore formation (Earnshaw and Rothfield 1985; including humans, have “regional” centromeres Earnshaw et al. 1986; Palmer et al. 1987, 1991; that span kilo- to megabases of highly repetitive Sullivan et al. 1994). In humans, functional cen- DNA. Importantly, in many eukaryotes, includ- tromeres always contain CENP-A, including ing humans, the underlying DNA sequence ap- “neocentromeres” that form on noncentromeric pears dispensable for centromere specification chromosomal loci (Saffery et al. 2000; Lo et al. and function. Instead, CENP-A nucleosomes 2001; Warburton, 2004). Experimental overex- appear to epigenetically define the centromere. pression of Drosophila CENP-ACID causes the The evidence for epigenetic specification ectopic localization of CENP-ACID to noncen- of higher eukaryotic centromeres is compel- tromere regions, which in turn causes ectopic ling. Sequence-driven centromere specification kinetochore formation and numerous mitotic would presumably impart significant selective errors (Heun et al. 2006). When CENP-ACID is
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