Diverse mechanisms of centromere specification

Abstract

The centromere performs a universally conserved function, to accurately partition genetic information upon cell division. Yet, centromeres are among the most rapidly evolving regions of the genome and are bound by a varying assortment of centromere-binding factors that are themselves highly divergent at the protein-sequence level. A common thread in most species is the dependence on the centromere-specific histone variant CENP-A for the specification of the centromere site. However, CENP-A is not universally required in all species or cell types, making the identification of a general mechanism for centromere specification challenging. In this review, we examine our current understanding of the mechanisms of centromere specification in CENP-A-dependent and independent systems, focusing primarily on recent work.

Figure 1.. Genetic and epigenetic factors control centromere position.

(A-C) Models for maintenance of human centromeres via CENP-A nucleosomes clustering (A), via a CENP-A self-assembly template mechanism (B) and via CENP-B/CENP-C interaction (C). (D-E) Models for de novo centromere formation of human centromeres via protein/protein interactions (D), changes in the epigenetics landscape (E) and presence of secondary structures and/or topological changes (F). Dashed lines denote proposed interactions, question marks represent untested interactions.

Figure 2.. Protein/protein interactions govern centromere identity.

Schematic map of reported protein-protein interactions between HJURP, CENP-B, CENP-C, CENP-A, M18BP1, Mis18α and Mis18β. Numbers indicate amino acid (aa) positions for each protein relative to their domains. Specific aa residues are also marked to highlight a particular PTM or interaction. HIKLMN are CENP proteins, CATD = CENP-A targeting domain, HCTD1/2 = HJURP C-terminal domain, SANT-A = SANT associated domain, green and red P = phosphorylation that lead to protein activation or inhibition, respectively. Top left inset: model for new CENP-A deposition based on an interplay of two CENP-C molecules to assemble a new CENP-A nucleosome at the centromere during early G1 phase.

Figure 3.. Centromere organization in model species.

Schematic showing the DNA organization for three multicellular species with fully sequenced centromeres, Drosophila melanogaster centromere 3, Zea Mays centromere 10 , and Homo sapiens centromere 8 . A) Drosophila melanogaster centromere 3 is composed of blocks of 10-mer (Prodsat) and 12-mer (dodeca) satellites flanking an island of complex DNA, named Giglio, containing the centromere-enriched enriched retroelement G2/Jockey-3 and the Ribosomal Intergenic Spacer (IGS). B) Z. mays centromere 10 includes two CentC enriched-clusters, called C1 and C2, separated by a retroelement enriched region devoid of CentC (NC). CRs are Centromeric Retroelements 1-6. C) H. sapiens centromere 8 is composed of flanking monomeric α-sat interspersed with Long Interspersed Elements (LINEs), Short Interspersed Elements (SINEs) and other human satellites surrounding a region containing α-sat Higher Order Repeats (HORs). Dotted lines represent intervening sequences with the same organization of those shown. The brackets demarcate the region of the centromere that contains CENP-A and its corresponding length.

Figure 4.. Centromere transcription.

Diagram depicting two ways that transcription has been shown to influence centromere function. A) In Drosophila, transcription facilitates histone exchange and CENP-A deposition through the destabilizing effect of transcribing RNA polymerase II (RNAPII) and the histone chaperone FACT, which are recruited by the CENP-A assembly factor CAL1. The elongation factor Spt6 prevents loss of pre-existing CENP-A. Analogous findings have been shown in S. pombe and human cells. B) In human cells, α-satellite (α-sat) transcripts localize to their site of origin in cis, promoting centromere integrity and the deposition of new CENP-A.