Dynamic molecular linkers of the genome: the first decade of SMC proteins

Abstract

Structural maintenance of chromosomes (SMC) proteins are chromosomal ATPases, highly conserved from bacteria to humans, that play fundamental roles in many aspects of higher-order chromosome organization and dynamics. In eukaryotes, SMC1 and SMC3 act as the core of the cohesin complexes that mediate sister chromatid cohesion, whereas SMC2 and SMC4 function as the core of the condensin complexes that are essential for chromosome assembly and segregation. Another complex containing SMC5 and SMC6 is implicated in DNA repair and checkpoint responses. The SMC complexes form unique ring-or V-shaped structures with long coiled-coil arms, and function as ATP-modulated, dynamic molecular linkers of the genome. Recent studies shed new light on the mechanistic action of these SMC machines and also expanded the repertoire of their diverse cellular functions. Dissecting this class of chromosomal ATPases is likely to be central to our understanding of the structural basis of genome organization, stability, and evolution.The chromosome is at the heart of all genetic processes. Its precise duplication and segregation are arguably the most important goal of the mitotic cell cycle, and programmed expression of its content, either genetic or epigenetic, is central to the development of an organism. While the astonishing advancement of genome biology in recent years has provided an advanced starting point for virtually all areas in biology, it does not solve an old problem in chromosome biology: How is the genomic DNA folded, organized, and segregated in the tiny space of a cell? The discovery of structural maintenance of chromosomes (SMC) proteins, almost a decade ago, provided a decisive clue to solve this longstanding question, and led to the identification of cohesin and condensins, two representative classes of SMC-containing complexes in eukaryotes. The proposed actions of cohesin and condensins offer a plausible, if not complete, explanation for the sudden appearance of thread-like "substances" (the chromosomes) and their longitudinal splitting during mitosis, first described by Walther Flemming (1882). Remarkably, SMC proteins are conserved among the three phyla of life, indicating that the basic strategy of chromosome organization may be evolutionarily conserved from bacteria to humans. An emerging theme is that SMC proteins are dynamic molecular linkers of the genome that actively fold, tether, and manipulate DNA strands. Their diverse functions range far beyond chromosome segregation, and involve nearly all aspects of chromosome behavior including chromosome-wide or long-range gene regulation and DNA repair. In this review article, we summarize our current understanding of SMC proteins with a major focus on studies published during the past three years. We start by describing the architecture and mechanistic actions of SMC protein complexes, and then discuss how the concerted actions of cohesin and condensin support the faithful segregation of chromosomes during mitosis and meiosis. Finally, emerging studies of a third S...

Transcriptional homogenization of rDNA repeats in the episome-based nucleolus induces genome-wide changes in the chromosomal distribution of condensin

“…Second, the uncovered degree of flexibility in the chromosomal location requirements for condensin binding may indicate that the fixed chromosomal position of these sites is not essential for overall chromosome condensation. This is consistent with the in vitro assay (Hirano, 2004;Losada and Hirano, 2005) showing that topological changes introduced into DNA molecule locally (at the condensin binding site) are then translated (via compensatory supercoiling) into whole-molecule topological changes. Third, the substantial relief of the essential condensin function in the segregation of rDNA (Wang et al, 2006) and the discovered here formation of an altered binding pattern across chromosomes, yet more reproducible and robust than in wild type, both make ErDNA cells an attractive experimental model with better approximation for condensin biology in higher eukaryotes.…”

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

“…SMC proteins are ABC-like ATPases, which typically associate with chromatin and contain a central coiled-coil and a dimerisation region. Examples of SMC heterodimers complexes include SMC1/SMC3 (cohesin) and SMC2/SMC4 (condensin), which are essential in sister chromatid attachment and chromosome assembly/segregation respectively (Losada and Hirano, 2005;Haering, and Nasmyth. 2003;.…”

Smc5–Smc6 complex suppresses gross chromosomal rearrangements mediated by break-induced replications

“…Although the main role of the Smc5-Smc6 complex is still unclear, recent studies have shown that this complex is recruited to the induced DNA double-strand-breaks (DSBs) [31,32] to enhance their repair by sister-chromatid recombination [31,32]. Smc5-6 heterodimer makes a multi-protein complex with six additional subunits in budding yeast (Nse1-6) [28]. Nse2 also known as Mms21 is an E3 SUMO ligase and several studies suggested that Mms21 links Smc5-6 to DNA repair role through sumoylation [33,34].…”

“…Eukaryotic cells have three protein complexes containing chromosomal ATPases of the Structural Maintenance of Chromosomes (SMC) family that function in various aspects of chromosome metabolism [26][27][28][29]. SMC complexes are characterized by the presence of a heterodimer of Smc proteins at the core with additional non-Smc subunits.…”