Emerging roles for centromeres in meiosis I chromosome segregation

Abstract

Centromeres are an essential and conserved feature of eukaryotic chromosomes, yet recent research indicates that we are just beginning to understand the numerous roles that centromeres have in chromosome segregation. During meiosis I, in particular, centromeres seem to function in many processes in addition to their canonical role in assembling kinetochores, the sites of microtubule attachment. Here we summarize recent advances that place centromeres at the centre of meiosis I, and discuss how these studies affect a variety of basic research fields and thus hold promise for increasing our understanding of human reproductive defects and disease states.

Figure 1. Comparison of mitosis and meiosis

(A) Mitosis is essentially a cycle of duplication and sorting. Cells double their genetic content and then must ensure that this content is divided such that each resultant cell gets exactly one copy of each chromosome. This is achieved through attachment of newly formed sister chromatids, central positioning of attached sisters, and a spindle that pulls one sister of each homolog to a given pole. We thus can think of the mitotic cell cycle as a repeating series of: “copy, attach_sisters, position_sisters, pull_sisters”. Note that for simplicity, only one pair of homologs is pictured here, represented in yellow and blue. (B) Meiosis, where the resultant cells need exactly one chromosome from a homolog pair, can then be similarly described as: “copy, attach_sisters, attach_homologs, position_homologs, pull_homologs, position_sisters, pull_sisters”. With this notation, it is clear that meiosis has three basic steps that are unique and require unique mechanisms to achieve. The “attach_homologs” step is achieved through pairing and recombination, the “position_homologs” step is through sister chromatid co-orientation, and the “pull_homologs” step occurs properly as a result of stepwise loss of cohesion.

Figure 2. Comparison of the centromeres of budding yeast, fission yeast and humans

(A) Budding yeast chromosomes average 780 kilobases, with a core centromere region of only 120 basepairs. Recent work shows a looped-out structure at the centromere that is similar to that seen in more complex eukaryotes. (B) Fission yeast chromosomes average 4.2 megabases with an average centromere size of 70 kilobases. The centromere consists of a central region (cen), surrounded by inner repeats (imr), which are in turn flanked by outer repeats (otr). Like budding yeast, the fission yeast centromere forms a loop-like structure that extends outward from chromosomes. (C) Human chromosomes average 143 megabases, with an average centromere size of 2.5 megabases, consisting primarily of tandem, degenerate 171 basepair α-satellite repeats (shown as green and blue bands). Note that chromosomes and centromeres are drawn roughly to scale.

Figure 3. Chromosome morphogenesis in meiotic prophase

Upon entry into meiosis, chromosomes are decondensed and homologs are not associated. Shortly after cells enter the meiotic program, chromosomes undergo DNA replication, during which sister chromatids are created and linked through cohesin complexes. Following DNA replication, during stages known as Leptotene and Zygotene, a number of events occur concomitantly: chromosomes begin to condense, double-strand breaks (DSBs) are formed throughout the genome, and homologous chromosomes associate through pairing. Paired homologs then undergo recombination and Synaptonemal Complex (SC) assembly, which is completed during pachytene stage as chromosomes reach a maximal level of condensation. In late prophase, in a stage known as diakinesis, homologs are attached through chiasmata to form bivalents, which will align at the center of the nucleus at metaphase I and serve as the basis for meiosis I reductional segregation. Note that for simplicity, only a single pair of homologs is pictured here. For reviews of early prophase processes, see , ,

Figure 4. Centromere clustering in prophase in budding yeast

This figure shows a S. cerevisiae cell with 16 centromeric foci, each consisting of two chromosomes (with two sister chromatids each) in early prophase. Centromeres are visualized through the kinetochore component Ctf19 (green) and SC component Zip1 (red). The large, irregular focus in the Zip1 channel is a polycomplex, a non-DNA associated complex of unassembled SC components. The cell shown is defective in recombination to prevent formation of recombination-dependent Zip1 foci that represent a separable function of Zip1. The images are generously supplied by Shirleen Roeder and are reprinted with permission from Science .

Figure 5. A model for the establishment of a protected domain of centromeric cohesion in budding yeast

The Sgo1-Bub1 complex, the protector of centromeric cohesion, is recruited to the core centromere by unknown mechanisms. Once at the centromere, kinetochore components including Iml3, Chl4, and centromere- proximal cohesins promote spreading of Sgo1 to pericentric regions. Sgo1 eventually occupies a domain that spans 50 kilobases around budding yeast centromeres, fully coinciding with the region of cohesion that is protected from removal during meiosis I. Note that cohesins are not anchored but rather are able to move along chromosomes, as depicted by arrows on either side of cohesin rings .

Figure 6. The role of kinetochore geometry in co-orientation in fission yeast

In fission yeast, Moa1 and centromeric cohesion cooperate to co-orient sister chromatids at meiosis I. In the absence of Moa1 (moa1Δ), sister chromatids are not correctly aligned to allow cohesion between sister centromeres, resulting in bi-orientation and equational segregation at meiosis I. In the absence of centromeric cohesion (lack of centromeric cohesion), Moa1 cannot functionally co-orient sister kinetochores, indicating that centromeric cohesion is key to sister kinetochore co-orientation and that Moa1 acts primarily to promote proper placement of centromeric cohesins. This figure is based on figures and data from .