Abstract
Maintenance of an intact genome is essential for cellular and organismal homeostasis. The centromere is a specialized chromosomal locus required for faithful genome inheritance at each round of cell division. Human centromeres are composed of large tandem arrays of repetitive alpha-satellite DNA, which are often sites of aberrant rearrangements that may lead to chromosome fusions and genetic abnormalities. While the centromere has an essential role in chromosome segregation during mitosis, the long and repetitive nature of the highly identical repeats has greatly hindered in-depth genetic studies, and complete annotation of all human centromeres is still lacking. Here, we review our current understanding of human centromere genetics and epigenetics as well as recent investigations into the role of centromere DNA in disease, with a special focus on cancer, aging, and human immunodeficiency–centromeric instability–facial anomalies (ICF) syndrome. We also highlight the causes and consequences of genomic instability at these large repetitive arrays and describe the possible sources of centromere fragility. The novel connection between alpha-satellite DNA instability and human pathological conditions emphasizes the importance of obtaining a truly complete human genome assembly and accelerating our understanding of centromere repeats’ role in physiology and beyond.
Highlights
The centromere is a specialized chromosomal locus required for faithful genome inheritance at each round of cell division
Chromosome segregation relies on the centromere, which connects chromosomes to the spindle microtubules that are responsible for separating sister chromatids
In addition to centromere specification, we have recently shown that CENP-A is involved in maintaining alpha-satellite DNA integrity in cycling human cells [54]
Summary
Cells are equipped with sophisticated molecular networks that ensure faithful transmission of genetic information at each round of cell division. In individuals heterozygous for the two epialleles, functional centromeres preferentially form on the array with less genetic variation [9], suggesting that sequence homogeneity promotes centromere assembly. The size of a particular array may vary by over an order of magnitude between individuals [10,11,12] This variation, surprisingly, does not seem to have an effect on mitotic centromere function and faithful chromosome segregation. In the regions flanking the centromere, the highly homogeneous HOR arrangement of alpha-satellite DNA becomes progressively more heterogeneous and unstructured. These regions are called pericentromeres and their organization and epigenetic makeup are distinct from centromeres. It is paradoxically necessary for formation of de novo centromeres on artificial chromosomes, but it is not essential for the formation of neocentromeres, and mice lacking CENP-B are viable and fertile [21,22]
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