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Sumoylation and the structural maintenance of chromosomes (Smc) 5/6 complex slow senescence through recombination intermediate resolution.

ABSTRACT: Telomeres are repetitive nucleoprotein structures that cap the ends of chromosomes. Without telomerase, telomeres shorten with replication and eventually signal cell cycle arrest (cell senescence). Homologous recombination (HR)-based mechanisms slow senescence, and distinct HR mechanisms support the growth of the rare survivors of senescence. Here, we report novel roles for the post-translational modification of small ubiquitin-like modifier (SUMO) in regulating the rate of senescence in Saccharomyces cerevisiae telomerase mutants. We identify Mms21 as the relevant SUMO E3 ligase and demonstrate that cells lacking Mms21-dependent sumoylation accumulate HR intermediates selectively at telomeres during senescence. One target of Mms21-dependent sumoylation is the cohesin- and condensin-related Smc5-Smc6 complex (Smc5/6). We show that hypomorphic smc5 or smc6 alleles exhibit phenotypes similar to mms21 sumoylation-deficient mutants with regard to senescence and the accumulation of unresolved HR intermediates. Further, we provide evidence that Mms21 and Smc5/6 prevent aberrant recombination between sister telomeres and also globally facilitate resolution of sister chromatid HR intermediates.

SUBMITTER: Chavez A

PROVIDER: S-EPMC2852929 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Homologous recombination-dependent rescue of deficiency in the structural maintenance of chromosomes (Smc) 5/6 complex.

Project description:The essential and evolutionarily conserved Smc5-Smc6 complex (Smc5/6) is critical for the maintenance of genome stability. Partial loss of Smc5/6 function yields several defects in DNA repair, which are rescued by inactivation of the homologous recombination (HR) machinery. Thus HR is thought to be toxic to cells with defective Smc5/6. Recent work has highlighted a role for Smc5/6 and the Sgs1 DNA helicase in preventing the accumulation of unresolved HR intermediates. Here we investigate how deletion of MPH1, encoding the orthologue of the human FANCM DNA helicase, rescues the DNA damage sensitivity of smc5/6 but not sgs1? mutants. We find that MPH1 deletion diminishes accumulation of HR intermediates within both smc5/6 and sgs1? cells, suggesting that MPH1 deletion is sufficient to decrease the use of template switch recombination (TSR) to bypass DNA lesions. We further explain how avoidance of TSR is nonetheless insufficient to rescue defects in sgs1? mutants, by demonstrating a requirement for Sgs1, along with the post-replicative repair (PRR) and HR machinery, in a pathway that operates in mph1? mutants. In addition, we map the region of Mph1 that binds Smc5, and describe a novel allele of MPH1 encoding a protein unable to bind Smc5 (mph1-?60). Remarkably, mph1-?60 supports normal growth and responses to DNA damaging agents, indicating that Smc5/6 does not simply restrain the recombinogenic activity of Mph1 via direct binding. These data as a whole highlight a role for Smc5/6 and Sgs1 in the resolution of Mph1-dependent HR intermediates.

| S-EPMC3037623 | biostudies-literature

Structural maintenance of chromosomes (SMC) proteins, a family of conserved ATPases.

Project description:SUMMARY:The structural maintenance of chromosomes (SMC) proteins are essential for successful chromosome transmission during replication and segregation of the genome in all organisms. SMCs are generally present as single proteins in bacteria, and as at least six distinct proteins in eukaryotes. The proteins range in size from approximately 110 to 170 kDa, and each has five distinct domains: amino- and carboxy-terminal globular domains, which contain sequences characteristic of ATPases, two coiled-coil regions separating the terminal domains and a central flexible hinge. SMC proteins function together with other proteins in a range of chromosomal transactions, including chromosome condensation, sister-chromatid cohesion, recombination, DNA repair and epigenetic silencing of gene expression. Recent studies are beginning to decipher molecular details of how these processes are carried out.

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Structural maintenance of chromosomes (SMC) proteins promote homolog-independent recombination repair in meiosis crucial for germ cell genomic stability.

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| S-EPMC2908675 | biostudies-literature

Dynamic architecture of the Escherichia coli structural maintenance of chromosomes (SMC) complex, MukBEF.

Project description:Ubiquitous Structural Maintenance of Chromosomes (SMC) complexes use a proteinaceous ring-shaped architecture to organize and individualize chromosomes, thereby facilitating chromosome segregation. They utilize cycles of adenosine triphosphate (ATP) binding and hydrolysis to transport themselves rapidly with respect to DNA, a process requiring protein conformational changes and multiple DNA contact sites. By analysing changes in the architecture and stoichiometry of the Escherichia coli SMC complex, MukBEF, as a function of nucleotide binding to MukB and subsequent ATP hydrolysis, we demonstrate directly the formation of dimer of MukBEF dimer complexes, dependent on dimeric MukF kleisin. Using truncated and full length MukB, in combination with MukEF, we show that engagement of the MukB ATPase heads on nucleotide binding directs the formation of dimers of heads-engaged dimer complexes. Complex formation requires functional interactions between the C- and N-terminal domains of MukF with the MukB head and neck, respectively, and MukE, which organizes the complexes by stabilizing binding of MukB heads to MukF. In the absence of head engagement, a MukF dimer bound by MukE forms complexes containing only a dimer of MukB. Finally, we demonstrate that cells expressing MukBEF complexes in which MukF is monomeric are Muk-, with the complexes failing to associate with chromosomes.

| S-EPMC6765140 | biostudies-literature

A novel structural maintenance of chromosomes (SMC)-related protein family specific to Archaea.

Project description:The ATPases belonging to the structural maintenance of chromosomes (SMC) superfamily are involved in the maintenance of chromosome organization and dynamics, as well as DNA repair. The major proteins in this superfamily recognized to date are either conserved among the three domains of Life (i.e., SMC and Rad50) or specific to Bacteria (i.e., RecF, RecN, and MukB). In Archaea, no protein related to SMC (SMC-related protein) with a broad taxonomic distribution has been reported. Nevertheless, two SMC-related proteins, namely coalescin and Sph, have been identified in crenarchaea Sulfolobus spp. and the euryarchaeon Halobacterium salinarum, respectively, hinting that the diversity of SMC-related proteins has been overlooked in Archaea. In this study, we report a novel SMC-related protein that is distributed among broad archaeal lineages and termed "Archaea-specific SMC-related proteins" or "ASRPs." We further demonstrate that the ASRP family encloses both coalescin and Sph but the two proteins represent only a tip of the diversity of this family.

| S-EPMC9389158 | biostudies-literature

Structural maintenance of chromosomes (SMC) proteins are required for DNA elimination in <i>Paramecium</i>.

Project description:Chromosome (SMC) proteins are a large family of ATPases that play important roles in the organization and dynamics of chromatin. They are central regulators of chromosome dynamics and the core component of condensin. DNA elimination during zygotic somatic genome development is a characteristic feature of ciliated protozoa such as Paramecium This process occurs after meiosis, mitosis, karyogamy, and another mitosis, which result in the formation of a new germline and somatic nuclei. The series of nuclear divisions implies an important role of SMC proteins in Paramecium sexual development. The relationship between DNA elimination and SMC has not yet been described. Here, we applied RNA interference, genome sequencing, mRNA sequencing, immunofluorescence, and mass spectrometry to investigate the roles of SMC components in DNA elimination. Our results show that SMC4-2 is required for genome rearrangement, whereas SMC4-1 is not. Functional diversification of SMC4 in Paramecium led to a formation of two paralogues where SMC4-2 acquired a novel, development-specific function and differs from SMC4-1. Moreover, our study suggests a competitive relationship between these two proteins.

| S-EPMC10700549 | biostudies-literature

Effects of the Structural Maintenance of Chromosomes (SMC) protein on gene expression in Bacillus subtilis

Project description:We monitored changes in Bacillus subtilis global gene expression in response to deletion or disruption of smc or ftsY. Keywords: genetic modification

2007-07-02 | GSE5210 | GEO

The symmetrical structure of structural maintenance of chromosomes (SMC) and MukB proteins: long, antiparallel coiled coils, folded at a flexible hinge.

Project description:Structural maintenance of chromosomes (SMC) proteins function in chromosome condensation and several other aspects of DNA processing. They are large proteins characterized by an NH2-terminal nucleotide triphosphate (NTP)-binding domain, two long segments of coiled coil separated by a hinge, and a COOH-terminal domain. Here, we have visualized by EM the SMC protein from Bacillus subtilis (BsSMC) and MukB from Escherichia coli, which we argue is a divergent SMC protein. Both BsSMC and MukB show two thin rods with globular domains at the ends emerging from the hinge. The hinge appears to be quite flexible: the arms can open up to 180 degrees, separating the terminal domains by 100 nm, or close to near 0 degrees, bringing the terminal globular domains together. A surprising observation is that the approximately 300-amino acid-long coiled coils are in an antiparallel arrangement. Known coiled coils are almost all parallel, and the longest antiparallel coiled coils known previously are 35-45 amino acids long. This antiparallel arrangement produces a symmetrical molecule with both an NH2- and a COOH-terminal domain at each end. The SMC molecule therefore has two complete and identical functional domains at the ends of the long arms. The bifunctional symmetry and a possible scissoring action at the hinge should provide unique biomechanical properties to the SMC proteins.

| S-EPMC2141774 | biostudies-literature

DNA-segment-capture model for loop extrusion by structural maintenance of chromosome (SMC) protein complexes.

Project description:Cells possess remarkable control of the folding and entanglement topology of long and flexible chromosomal DNA molecules. It is thought that structural maintenance of chromosome (SMC) protein complexes play a crucial role in this, by organizing long DNAs into series of loops. Experimental data suggest that SMC complexes are able to translocate on DNA, as well as pull out lengths of DNA via a 'loop extrusion' process. We describe a Brownian loop-capture-ratchet model for translocation and loop extrusion based on known structural, catalytic, and DNA-binding properties of the Bacillus subtilis SMC complex. Our model provides an example of a new class of molecular motor where large conformational fluctuations of the motor 'track'-in this case DNA-are involved in the basic translocation process. Quantitative analysis of our model leads to a series of predictions for the motor properties of SMC complexes, most strikingly a strong dependence of SMC translocation velocity and step size on tension in the DNA track that it is moving along, with 'stalling' occuring at subpiconewton tensions. We discuss how the same mechanism might be used by structurally related SMC complexes (Escherichia coli MukBEF and eukaryote condensin, cohesin and SMC5/6) to organize genomic DNA.

| S-EPMC6649773 | biostudies-literature

SOS induction in a subpopulation of structural maintenance of chromosome (Smc) mutant cells in Bacillus subtilis.

Project description:The structural maintenance of chromosome (Smc) protein is highly conserved and involved in chromosome compaction, cohesion, and other DNA-related processes. In Bacillus subtilis, smc null mutations cause defects in DNA supercoiling, chromosome compaction, and chromosome partitioning. We investigated the effects of smc mutations on global gene expression in B. subtilis using DNA microarrays. We found that an smc null mutation caused partial induction of the SOS response, including induction of the defective prophage PBSX. Analysis of SOS and phage gene expression in single cells indicated that approximately 1% of smc mutants have fully induced SOS and PBSX gene expression while the other 99% of cells appear to have little or no expression. We found that induction of PBSX was not responsible for the chromosome partitioning or compaction defects of smc mutants. Similar inductions of the SOS response and PBSX were observed in cells depleted of topoisomerase I, an enzyme that relaxes negatively supercoiled DNA.

| S-EPMC1913351 | biostudies-literature

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