Cohesin: a regulator of genome integrity and gene expression

2010 ◽  
Vol 428 (2) ◽  
pp. 147-161 ◽  
Author(s):  
Katherine M. Feeney ◽  
Christopher W. Wasson ◽  
Joanna L. Parish
Keyword(s):  
Gene Expression ◽  
Chromosome Segregation ◽  
Sister Chromatid ◽  
Dna Lesions ◽  
Genome Integrity ◽  
Accessory Proteins ◽  
Post Translational Modification ◽  
Control Of Gene Expression ◽  
Chromatid Cohesion ◽  
And Control

Following DNA replication, chromatid pairs are held together by a proteinacious complex called cohesin until separation during the metaphase-to-anaphase transition. Accurate segregation is achieved by regulation of both sister chromatid cohesion establishment and removal, mediated by post-translational modification of cohesin and interaction with numerous accessory proteins. Recent evidence has led to the conclusion that cohesin is also vitally important in the repair of DNA lesions and control of gene expression. It is now clear that chromosome segregation is not the only important function of cohesin in the maintenance of genome integrity.

scholarly journals Brca2, Pds5 and Wapl differentially control cohesin chromosome association and function

2017 ◽  
Author(s):  
Ziva Misulovin ◽  
Michelle Pherson ◽  
Maria Gause ◽  
Dale Dorsett
Keyword(s):  
Gene Expression ◽  
Dna Repair ◽  
Dna Replication ◽  
Chromosome Segregation ◽  
Sister Chromatid ◽  
Protein Complex ◽  
Sister Chromatid Cohesion ◽  
Sister Chromatids ◽  
Chromatid Cohesion ◽  
Active Genes

AbstractThe cohesin complex topologically encircles chromosomes and mediates sister chromatid cohesion to ensure accurate chromosome segregation upon cell division. Cohesin also participates in DNA repair and gene transcription. The Nipped-B – Mau2 protein complex loads cohesin onto chromosomes and the Pds5 - Wapl complex removes cohesin. Pds5 is also essential for sister chromatid cohesion, indicating that it has functions beyond cohesin removal. The Brca2 DNA repair protein interacts with Pds5, but the roles of this complex beyond DNA repair are unknown. Here we show that Brca2 opposes Pds5 function in sister chromatid cohesion by assaying precocious sister chromatid separation in metaphase spreads of cultured cells depleted for these proteins. By genome-wide chromatin immunoprecipitation we find that Pds5 facilitates SA cohesin subunit association with DNA replication origins and that Brca2 inhibits SA binding, mirroring their effects on sister chromatid cohesion. Cohesin binding is maximal at replication origins and extends outward to occupy active genes and regulatory sequences. Pds5 and Wapl, but not Brca2, limit the distance that cohesin extends from origins, thereby determining which active genes, enhancers and silencers bind cohesin. Using RNA-seq we find that Brca2, Pds5 and Wapl influence the expression of most genes sensitive to Nipped-B and cohesin, largely in the same direction. These findings demonstrate that Brca2 regulates sister chromatid cohesion and gene expression in addition to its canonical role in DNA repair and expand the known functions of accessory proteins in cohesin’s diverse functions.Author summaryThe cohesin protein complex has multiple functions in eukaryotic cells. It ensures that when a cell divides, the two daughter cells receive the correct number of chromosomes. It does this by holding together the sister chromatids that are formed when chromosomes are duplicated by DNA replication. Cohesin also helps repair damaged DNA, and to regulate genes important for growth and development. Even minor deficiencies in some proteins that regulate cohesin cause significant human birth defects. Here we investigated in Drosophila cells how three proteins, Pds5, Wapl and Brca2, determine where cohesin binds to chromosomes, control cohesin’s ability to hold sister chromatids together, and participate in gene expression. We find that Pds5 and Wapl work together, likely during DNA replication, to determine which genes bind cohesin by controlling how far cohesin spreads out along chromosomes. Pds5 is required for cohesin to hold sister chromatids together, and Brca2 counteracts this function. In contrast to the opposing roles in sister chromatid cohesion, Pds5 and Brca2 work together to facilitate control of gene expression by cohesin. Brca2 plays a critical role in DNA repair, and these studies expand the known roles for Brca2 by showing that it also regulates sister chromatid cohesion and gene expression. BRCA2 mutations in humans increase susceptibility to breast and ovarian cancer, and these findings raise the possibility that changes in chromosome segregation or gene expression might contribute to the increased cancer risk associated with these mutations.

scholarly journals Cohesinopathies, gene expression, and chromatin organization

2010 ◽  
Vol 189 (2) ◽  
pp. 201-210 ◽  
Author(s):  
Tania Bose ◽  
Jennifer L. Gerton
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Chromosome Segregation ◽  
Sister Chromatid ◽  
Protein Complex ◽  
Genome Organization ◽  
Mammalian Cells ◽  
Dna Interactions ◽  
Developmental Defects ◽  
Chromatid Cohesion

The cohesin protein complex is best known for its role in sister chromatid cohesion, which is crucial for accurate chromosome segregation. Mutations in cohesin proteins or their regulators have been associated with human diseases (termed cohesinopathies). The developmental defects observed in these diseases indicate a role for cohesin in gene regulation distinct from its role in chromosome segregation. In mammalian cells, cohesin stably interacts with specific chromosomal sites and colocalizes with CTCF, a protein that promotes long-range DNA interactions, implying a role for cohesin in genome organization. Moreover, cohesin defects compromise the subnuclear position of chromatin. Therefore, defects in the cohesin network that alter gene expression and genome organization may underlie cohesinopathies.

scholarly journals Multiple Subunits of the Caenorhabditis elegans Anaphase-Promoting Complex Are Required for Chromosome Segregation During Meiosis I

Genetics ◽  
2002 ◽  
Vol 160 (2) ◽  
pp. 805-813 ◽  
Author(s):  
Edward S Davis ◽  
Lucia Wille ◽  
Barry A Chestnut ◽  
Penny L Sadler ◽  
Diane C Shakes ◽  
...  
Keyword(s):  
Rna Interference ◽  
Caenorhabditis Elegans ◽  
Chromosome Segregation ◽  
Sister Chromatid ◽  
Sister Chromatid Cohesion ◽  
Anaphase Promoting Complex ◽  
Genetic Screens ◽  
Chromatid Cohesion ◽  
Interference Studies ◽  
Meiosis I

Abstract Two genes, originally identified in genetic screens for Caenorhabditis elegans mutants that arrest in metaphase of meiosis I, prove to encode subunits of the anaphase-promoting complex or cyclosome (APC/C). RNA interference studies reveal that these and other APC/C subunits are essential for the segregation of chromosomal homologs during meiosis I. Further, chromosome segregation during meiosis I requires APC/C functions in addition to the release of sister chromatid cohesion.

scholarly journals Double or nothing: a Drosophila mutation affecting meiotic chromosome segregation in both females and males.

Genetics ◽  
1994 ◽  
Vol 136 (3) ◽  
pp. 953-964 ◽  
Author(s):  
D P Moore ◽  
W Y Miyazaki ◽  
J E Tomkiel ◽  
T L Orr-Weaver
Keyword(s):  
Cell Death ◽  
Chromosome Segregation ◽  
Sister Chromatid ◽  
Meiotic Chromosome ◽  
Sister Chromatid Cohesion ◽  
Aberrant Chromosome ◽  
Chromatid Cohesion ◽  
Meiotic Nondisjunction ◽  
Lethal Allele ◽  
Meiosis I

Abstract We describe a Drosophila mutation, Double or nothing (Dub), that causes meiotic nondisjunction in a conditional, dominant manner. Previously isolated mutations in Drosophila specifically affect meiosis either in females or males, with the exception of the mei-S332 and ord genes which are required for proper sister-chromatid cohesion. Dub is unusual in that it causes aberrant chromosome segregation almost exclusively in meiosis I in both sexes. In Dub mutant females both nonexchange and exchange chromosomes undergo nondisjunction, but the effect of Dub on nonexchange chromosomes is more pronounced. Dub reduces recombination levels slightly. Multiple nondisjoined chromosomes frequently cosegregate to the same pole. Dub results in nondisjunction of all chromosomes in meiosis I of males, although the levels are lower than in females. When homozygous, Dub is a conditional lethal allele and exhibits phenotypes consistent with cell death.

scholarly journals A quantitative analysis of cohesin decay in mitotic fidelity

2018 ◽  
Vol 217 (10) ◽  
pp. 3343-3353 ◽  
Author(s):  
Sara Carvalhal ◽  
Alexandra Tavares ◽  
Mariana B. Santos ◽  
Mihailo Mirkovic ◽  
Raquel A. Oliveira
Keyword(s):  
Quantitative Analysis ◽  
Chromosome Segregation ◽  
Sister Chromatid ◽  
Mitotic Spindle ◽  
Sister Chromatid Cohesion ◽  
Force Balance ◽  
Chromosome Organization ◽  
Centromeric Chromatin ◽  
Chromatid Cohesion ◽  
Chromosome Alignment

Sister chromatid cohesion mediated by cohesin is essential for mitotic fidelity. It counteracts spindle forces to prevent premature chromatid individualization and random genome segregation. However, it is unclear what effects a partial decline of cohesin may have on chromosome organization. In this study, we provide a quantitative analysis of cohesin decay by inducing acute removal of defined amounts of cohesin from metaphase-arrested chromosomes. We demonstrate that sister chromatid cohesion is very resistant to cohesin loss as chromatid disjunction is only observed when chromosomes lose >80% of bound cohesin. Removal close to this threshold leads to chromosomes that are still cohered but display compromised chromosome alignment and unstable spindle attachments. Partial cohesin decay leads to increased duration of mitosis and susceptibility to errors in chromosome segregation. We propose that high cohesin density ensures centromeric chromatin rigidity necessary to maintain a force balance with the mitotic spindle. Partial cohesin loss may lead to chromosome segregation errors even when sister chromatid cohesion is fulfilled.

scholarly journals ConnectingGCN5’s centromeric SAGA to the mitotic tension-sensing checkpoint

2018 ◽  
Vol 29 (18) ◽  
pp. 2201-2212 ◽  
Author(s):  
Emily L. Petty ◽  
Masha Evpak ◽  
Lorraine Pillus
Keyword(s):  
Chromosome Segregation ◽  
Sister Chromatid ◽  
Spindle Assembly Checkpoint ◽  
Binding Function ◽  
Chromatid Cohesion ◽  
Histone H3 Variant ◽  
Spindle Microtubules ◽  
Low Tension ◽  
Centromere Histone H3 ◽  
Segregation Of Chromosomes

Multiple interdependent mechanisms ensure faithful segregation of chromosomes during cell division. Among these, the spindle assembly checkpoint monitors attachment of spindle microtubules to the centromere of each chromosome, whereas the tension-sensing checkpoint monitors the opposing forces between sister chromatid centromeres for proper biorientation. We report here a new function for the deeply conserved Gcn5 acetyltransferase in the centromeric localization of Rts1, a key player in the tension-sensing checkpoint. Rts1 is a regulatory component of protein phopshatase 2A, a near universal phosphatase complex, which is recruited to centromeres by the Shugoshin (Sgo) checkpoint component under low-tension conditions to maintain sister chromatid cohesion. We report that loss of Gcn5 disrupts centromeric localization of Rts1. Increased RTS1 dosage robustly suppresses gcn5∆ cell cycle and chromosome segregation defects, including restoration of Rts1 to centromeres. Sgo1’s Rts1-binding function also plays a key role in RTS1 dosage suppression of gcn5∆ phenotypes. Notably, we have identified residues of the centromere histone H3 variant Cse4 that function in these chromosome segregation-related roles of RTS1. Together, these findings expand the understanding of the mechanistic roles of Gcn5 and Cse4 in chromosome segregation.

Organization of Chromosomal DNA by SMC Complexes

2019 ◽  
Vol 53 (1) ◽  
pp. 445-482 ◽  
Author(s):  
Stanislau Yatskevich ◽  
James Rhodes ◽  
Kim Nasmyth
Keyword(s):  
Chromosome Segregation ◽  
Sister Chromatid ◽  
Mitotic Chromosome ◽  
Sister Chromatid Cohesion ◽  
Chromosomal Dna ◽  
Chromosome Architecture ◽  
Chromatid Cohesion ◽  
Dna Translocases ◽  
Structural Maintenance Of Chromosomes

Structural maintenance of chromosomes (SMC) complexes are key organizers of chromosome architecture in all kingdoms of life. Despite seemingly divergent functions, such as chromosome segregation, chromosome maintenance, sister chromatid cohesion, and mitotic chromosome compaction, it appears that these complexes function via highly conserved mechanisms and that they represent a novel class of DNA translocases.

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