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Centromeres: Assembling and Propagating Epigenetic Function

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Genome Stability and Human Diseases

Part of the book series: Subcellular Biochemistry ((SCBI,volume 50))

Abstract

The faithful replication of DNA and the accurate segregation of genomic material from one generation to the next is critical in the maintenance of genomic stability. This chapter will describe the structure and assembly of an epigenetically inherited locus, the centromere, and its role in the processes by which sister chromatids are evenly segregated to daughter cells. During the G2 phase of the cell cycle kinetochores are assembled upon the chromatids. During mitosis, kinetochores attach chromosome(s) to the mitotic spindle. The kinetochore structure serves as the interface between the mitotic spindle and the chromatids and it is at the kinetochore where the forces that drive chromatid separation are generated. Unattached chromosomes fail to satisfy the spindle assembly checkpoint (SAC), resulting in cell cycle arrest. The centromere is the locus upon which the kinetochore assembles, and centromeres themselves are determined by their unique protein composition. Apart from budding yeast, centromeres are not specified simply by DNA sequence, but rather through chromatin composition and architecture and are thus epigenetically determined. Centromeres are built on a specific nucleosome not found elsewhere in the genome, in which histone H3 is replaced with a homologue – CENP-A or CenH3. This domain is flanked by heterochromatin and is folded to provide a 3-dimensional cylinder-like structure at metaphase that establishes the kinetochore on the surface of the mitotic chromosomes. A large family of CENtromere Proteins (CENPs) associates with centromeric chromatin throughout the cell cycle and are required for kinetochore function. Unlike the bulk of histones, CENP-A is not assembled concurrently with DNA synthesis in S-phase but rather assembles into the centromere in the subsequent G1 phase. The assembly of CENP-A chromatin following DNA replication and the re-establishment of this network of constitutive proteins have emerged as critical mechanisms for understanding how the centromere is replicated during the cell cycle.

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Abbreviations

APC/C:

Anaphase Promoting Complex-Cyclosome

BUB:

Budding Uninhibited by Benzimidazole

CAD:

CENP-A Distal Complex

CAF1:

Chromatin Assembly Factor

CATD:

CENP-A Targeting Domain

CCAN:

Constitutive Centromere-Associated Network

CENP:

Centromere Protein

HAT1:

Histone AcetylTransferase catalytic subunit

HFD:

Histone Fold Domain

hFLEG1:

human Fetal Liver Expressing Gene 1

Hir1:

HIRA like histone chaperone

KMN:

Knl1-Mis12-Ndc80 complex

MAD:

Mitotic-Arrested Deficient

MCC:

Mitotic Checkpoint Complex

MPS1:

Multipolar Spindle 1

NAC:

Nucleosome Associated Complex

PEV:

Position Effect Variegation

PRC2:

Polycomb Repressive Complex 2

RZZ:

ROD-ZW10-Zwilch Complex

SAC:

Spindle Assembly Checkpoint

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Authors and Affiliations

  1. Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland, Galway, Galway, Ireland

    Macdara Glynn, Agnieszka Kaczmarczyk, Lisa Prendergast & Nadine Quinn

  2. Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland, Galway, University Rd, Galway, Ireland

    Kevin F. Sullivan

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  1. Macdara Glynn
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  2. Agnieszka Kaczmarczyk
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  3. Lisa Prendergast
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    Heinz-Peter Nasheuer

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Glynn, M., Kaczmarczyk, A., Prendergast, L., Quinn, N., Sullivan, K.F. (2010). Centromeres: Assembling and Propagating Epigenetic Function. In: Nasheuer, HP. (eds) Genome Stability and Human Diseases. Subcellular Biochemistry, vol 50. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-3471-7_12

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