Chapter 5 Mechanisms of Sister Chromatid Pairing

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Abstract

The continuance of life through cell division requires high fidelity DNA replication and chromosome segregation. During DNA replication, each parental chromosome is duplicated exactly and one time only. At the same time, the resulting chromosomes (called sister chromatids) become tightly paired along their length. This S‐phase pairing, or cohesion, identifies chromatids as sisters over time. During mitosis in most eukaryotes, sister chromatids bi‐orient to the mitotic spindle. After each chromosome pair is properly oriented, the cohesion established during S phase is inactivated in a tightly regulated fashion, allowing sister chromatids to segregate away from each other. Recent findings of cohesin structure and enzymology provide new insights into cohesion, while many critical facets of cohesion (how cohesins tether together sister chromatids and how those tethers are established) remain actively debated.

Introduction

Cells divide to replenish loss caused by trauma, cell senescence and cell death. Cell division also provides for embryonic growth, tissue regeneration and remodeling. Whether simple unicellular or multi‐tissued organisms, the fundamental goal of cell division is to produce two viable and identical daughter cells. Continued viability of cell progeny requires that the DNA complement is replicated and that sister chromatids segregate into the newly forming daughter cells.

In eukaryotes, DNA replication and sister chromatid segregation are temporally separated. For instance, checkpoints delay cell‐cycle progression until each chromosome is fully replicated and physically intact. The G2 phase further separates S phase from mitosis (chromosome segregation), allowing for further growth and maturation prior to cell division. The consequence of temporally separating replication from segregation is that sister chromatids generated during S phase must retain their identity as sisters until anaphase.

The processes that identify sister chromatids, tether them together and maintain this tether from early S phase until anaphase onset fall under the general term sister chromatid cohesion. Cohesion requires coordinated activities of at least four different classes of proteins: structural cohesins, deposition complexes, establishment factors and cohesion regulators. Here, structural cohesins refers to those factors that directly resist poleward‐directed kinetochore/spindle forces that are exerted on each sister chromatid. Deposition factors are required for structural cohesins to associate with chromatin. As we will see, proper deposition and the presence of structural cohesins on chromosomes are not sufficient for sister chromatid pairing. A third and essential activity, Establishment, is required. Many researchers extend the role of deposition factors to include establishment. While such views may simplify matters, they do so at the expense of accuracy. Deposition and establishment are indeed quite separate—a position substantiated by the fact that each requires independent complexes and that these processes can be genetically separated by mutational analyses. The fourth class is cohesion regulators that support cohesion and/or promote structural cohesin dynamics.

Pairings between sister chromatids cannot be static. Soluble cohesin complexes are undoubtedly modified to promote deposition onto chromatin. Chromatin‐associated cohesins in turn appear to move away from these deposition sites and set up residence at functional cohesion sites. Cohesins are further modified to affect sister chromatid pairing. The nature of this pairing remains highly controversial. Cohesin dynamics must also accommodate condensation—a progressive contraction that reduces the chromosome length but also produces ever‐decreasing contact points between sister chromatids (Guacci et al., 1994, Selig et al., 1992, Sumner, 1991). Little is known regarding how cohesin subsets are inactived to accommodate continued condensation while another set persists to maintain sister chromatid pairing. Add to the list cohesin dissociation pathways. In higher eukaryotes, a predominant fraction of cohesins disassociate from chromatin in early prophase with the remaining cohesins dissociating at anaphase onset. Cohesin release during prophase relies on phosphorylation while release during anaphase onset occurs predominantly through proteolysis (Nasmyth et al., 2000, Wang and Dai, 2005, Watanabe, 2005, Yanagida, 2005). Thus, there are numerous and separate pathways that regulate cohesin dynamics—not all of which are present in every organism.

In this review, I focus on mechanisms used by budding yeast to identify and then pair together sister chromatids. The review starts with a discussion on the physical characteristics of structural cohesins and continues with recent models of cohesin enzymology. From this foundation, the review turns to factors that influence cohesin deposition and, subsequent to deposition—how cohesion is established between sister chromatids. I then highlight recent findings of alternate (non‐cohesin) sister pairing complexes and end with a discussion regarding advances in linking cohesion pathways to human disease states.

Section snippets

Structural Cohesins

Cohesins are required from the beginning of S phase until anaphase onset, but at no time is their presence more obvious than during mitosis when sister chromatids orient to spindle microtubules and, in a tug of war, oscillate back and forth across the spindle equator (Bajer, 1982, Goshima and Yanagida, 2000, He et al., 2000, Pearson et al., 2004, Rieder et al., 1986, Skibbens and Hieter, 1998, Waters et al., 1996). Kinetochore motility and the checkpoint system that regulates both mitotic exit

Cohesin Enzymology

Since the earliest characterization of a Structural Maintenance of Chromosome protein, or SMC (originally termed Stability of MiniChromosomes) (Lara‐Pezzi et al., 2004, Strunnikov et al., 1993), analyses of Smc1,3 enzymology produced a confusion of models that remain actively debated in the literature. Most models are predicated on the notions that (1) cohesins assemble into soluble structures—often depicted as rings, (2) subunit contact sites are disrupted for cohesin deposition, and (3)

Deposition—Scc2 and Scc4

Two slices of bread can be adhered together simply by slathering on sandwich spread (peanut butter, vegemite, etc.). Does such an analogy apply to cohesin deposition and sister chromatid pairing? The differences highlight important aspects of chromosome segregation. For instance, cohesins are not spread along the chromosome length but instead occur only at discrete sites positioned at roughly 10–12kb intervals (Blat and Kleckner, 1999, Glynn et al., 2004, Laloraya et al., 2000, Larionov et al.,

Pds5 in cohesion

In budding yeast, PDS5 was identified in a screen for temperature sensitive mutant strains that exhibited enhanced G2/M lethality (Hartman et al., 2000). Analyses of PDS5 was also prompted by Pds5 orthologs BIMD in A. nidulans and SPO76 in Sordaria macrospora. These factors either bind mitotic chromosomes, associate with SMC‐like proteins or prevent mitotic catastrophes and genotoxic sensitivity (Denison and May, 1994, Denison et al., 1993, Holt and May, 1996, Huynh et al., 1986, Panizza et

Cohesion Establishment and CTF7

Establishment is quite different from cohesin deposition and cohesion maintenance in that the latter two activities are insufficient to form sister chromatid pairing bonds. Here, I address the question “how is cohesion established between nascent sister chromatids?” The answer revolves around both cohesin structure and the only essential establishment factor identified to date—Ctf7/Eco1. CTF7 as a complementation group was first identified from a collection of mutants that exhibited defects in

ORCs

Even early studies foretold a role for non‐cohesins in sister chromatid pairing. Loss of structural cohesins results in only 50–60% cohesion defects at both centromere proximal and distal loci (Guacci et al., 1997, Meluh and Koshland, 1995, Toth et al., 1999). Why not 100%? In fact, analyses of cohesion defects at telomeres produced roughly 100% pairing defects in these same mutant alleles (Antoniacci and Skibbens, 2006). Thus, at least for telomeres, cohesins are the only game in town. That

Human Disease States and Future Considerations

Each of the four cohesion‐related processes (deposition, maintenance, dissolution, and establishment) are essential and required for proper chromosome segregation. Thus, it is not surprising that each is linked to clinical manifestations including developmental abnormalities (Dorsett, 2007). For instance, Cornelia de Lange Syndrome is produced by mutation of either human Scc2/NIPBL or Smc1 (Krantz et al., 2004, Musio et al., 2006, Tonkin et al., 2004). Cornelia de Lange Syndrome (CdLS)

Acknowledgments

Writing a review of this scope requires the cooperation of the research community as a whole. RVS thankfully acknowledges those collegues who provided access to data and information prior to publication: Drs. Katsuhiko Shirahige and Alex Brands. I am also deeply indebted to Drs. Orna Cohen‐Fix, Lynne Cassimeris, Paul Megee, Munira Basrai and lab members Marie Maradeo and Laura Eastman for performing the thankless task of editing early drafts and to Dr. Doug Koshland for helpful discussions.

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