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Molecular Cell Sep 2023Cohesin connects CTCF-binding sites and other genomic loci in cis to form chromatin loops and replicated DNA molecules in trans to mediate sister chromatid cohesion....
Cohesin connects CTCF-binding sites and other genomic loci in cis to form chromatin loops and replicated DNA molecules in trans to mediate sister chromatid cohesion. Whether cohesin uses distinct or related mechanisms to perform these functions is unknown. Here, we describe a cohesin hinge mutant that can extrude DNA into loops but is unable to mediate cohesion in human cells. Our results suggest that the latter defect arises during cohesion establishment. The observation that cohesin's cohesion and loop extrusion activities can be partially separated indicates that cohesin uses distinct mechanisms to perform these two functions. Unexpectedly, the same hinge mutant can also not be stopped by CTCF boundaries as well as wild-type cohesin. This suggests that cohesion establishment and cohesin's interaction with CTCF boundaries depend on related mechanisms and raises the possibility that both require transient hinge opening to entrap DNA inside the cohesin ring.
Topics: Humans; Chromatids; Binding Sites; Cell Cycle Proteins; Chromosomal Proteins, Non-Histone; Cohesins
PubMed: 37591243
DOI: 10.1016/j.molcel.2023.07.024 -
Nature Structural & Molecular Biology Jun 2023In the early stages of mitosis, cohesin is released from chromosome arms but not from centromeres. The protection of centromeric cohesin by SGO1 maintains the sister...
In the early stages of mitosis, cohesin is released from chromosome arms but not from centromeres. The protection of centromeric cohesin by SGO1 maintains the sister chromatid cohesion that resists the pulling forces of microtubules until all chromosomes are attached in a bipolar manner to the mitotic spindle. Here we present the X-ray crystal structure of a segment of human SGO1 bound to a conserved surface of the cohesin complex. SGO1 binds to a composite interface formed by the SA2 and SCC1 subunits of cohesin. SGO1 shares this binding interface with CTCF, indicating that these distinct chromosomal regulators control cohesin through a universal principle. This interaction is essential for the localization of SGO1 to centromeres and protects centromeric cohesin against WAPL-mediated cohesin release. SGO1-cohesin binding is maintained until the formation of microtubule-kinetochore attachments and is required for faithful chromosome segregation and the maintenance of a stable karyotype.
Topics: Humans; HeLa Cells; Centromere; Cell Cycle Proteins; Kinetochores; Mitosis; Chromosome Segregation; Chromatids
PubMed: 37081319
DOI: 10.1038/s41594-023-00968-y -
Genes & Development Apr 2023Cohesin is an ATPase that drives chromosome organization through the generation of intramolecular loops and sister chromatid cohesion. Cohesin's ATPase is stimulated by... (Review)
Review
Cohesin is an ATPase that drives chromosome organization through the generation of intramolecular loops and sister chromatid cohesion. Cohesin's ATPase is stimulated by Scc2 binding but attenuated by acetylation of its Smc3 subunit. In this issue of , Boardman and colleagues (pp. 277-290) take a genetic approach to generate a mechanistic model for the opposing regulation of cohesin's ATPase by Scc2 and Smc3 acetylation. Their findings provide in vivo insight into how this important genome organizer functions in vivo.
Topics: Adenosine Triphosphatases; Cell Cycle Proteins; Chromatin; Chromatids; Saccharomyces cerevisiae Proteins
PubMed: 37045607
DOI: 10.1101/gad.350627.123 -
Nucleic Acids Research Jun 2023Besides entrapping sister chromatids, cohesin drives other high-order chromosomal structural dynamics like looping, compartmentalization and condensation. ESCO2...
Besides entrapping sister chromatids, cohesin drives other high-order chromosomal structural dynamics like looping, compartmentalization and condensation. ESCO2 acetylates a subset of cohesin so that cohesion must be established and only be established between nascent sister chromatids. How this process is precisely achieved remains unknown. Here, we report that GSK3 family kinases provide higher hierarchical control through an ESCO2 regulator, CRL4MMS22L. GSK3s phosphorylate Thr105 in MMS22L, resulting in homo-dimerization of CRL4MMS22L and ESCO2 during S phase as evidenced by single-molecule spectroscopy and several biochemical approaches. A single phospho-mimicking mutation on MMS22L (T105D) is sufficient to mediate their dimerization and rescue the cohesion defects caused by GSK3 or MMS22L depletion, whereas non-phosphorylable T105A exerts dominant-negative effects even in wildtype cells. Through cell fractionation and time-course measurements, we show that GSK3s facilitate the timely chromatin association of MMS22L and ESCO2 and subsequently SMC3 acetylation. The necessity of ESCO2 dimerization implicates symmetric control of cohesion establishment in eukaryotes.
Topics: Acetyltransferases; Cell Cycle Proteins; Chromatids; Chromosome Segregation; Glycogen Synthase Kinase 3; Nuclear Proteins; S Phase; Humans; Cell Line; Yeasts; Chromosomal Proteins, Non-Histone; Cohesins
PubMed: 36912084
DOI: 10.1093/nar/gkad146 -
International Journal of Molecular... Mar 2021Several lines of evidence suggest the existence in the eukaryotic cells of a tight, yet largely unexplored, connection between DNA replication and sister chromatid... (Review)
Review
Several lines of evidence suggest the existence in the eukaryotic cells of a tight, yet largely unexplored, connection between DNA replication and sister chromatid cohesion. Tethering of newly duplicated chromatids is mediated by cohesin, an evolutionarily conserved hetero-tetrameric protein complex that has a ring-like structure and is believed to encircle DNA. Cohesin is loaded onto chromatin in telophase/G1 and converted into a cohesive state during the subsequent S phase, a process known as cohesion establishment. Many studies have revealed that down-regulation of a number of DNA replication factors gives rise to chromosomal cohesion defects, suggesting that they play critical roles in cohesion establishment. Conversely, loss of cohesin subunits (and/or regulators) has been found to alter DNA replication fork dynamics. A critical step of the cohesion establishment process consists in cohesin acetylation, a modification accomplished by dedicated acetyltransferases that operate at the replication forks. Defects in cohesion establishment give rise to chromosome mis-segregation and aneuploidy, phenotypes frequently observed in pre-cancerous and cancerous cells. Herein, we will review our present knowledge of the molecular mechanisms underlying the functional link between DNA replication and cohesion establishment, a phenomenon that is unique to the eukaryotic organisms.
Topics: Animals; Cell Cycle Proteins; Chromatids; Chromosomal Proteins, Non-Histone; Chromosome Segregation; DNA Replication; G1 Phase; Humans; Telophase; Cohesins
PubMed: 33802105
DOI: 10.3390/ijms22062810 -
Genes & Development Nov 2017Cohesin was identified through its major role in holding sister chromatids together. We are learning through analysis of cohesin and other members of the protein family... (Review)
Review
Cohesin was identified through its major role in holding sister chromatids together. We are learning through analysis of cohesin and other members of the protein family (SMC [structural maintenance of chromosomes]) and their regulators that these ring complexes contribute to chromosome organization and dynamics throughout the cell cycle. We need to consider not only how ring complexes are regulated but how they interact with their fluctuating chromatin substrate.
Topics: Acetyltransferases; Cell Cycle Proteins; Chromatids; Chromatin; Chromosomal Proteins, Non-Histone; Interphase; Cohesins
PubMed: 29237741
DOI: 10.1101/gad.309732.117 -
Cells Dec 2021The cohesin complex facilitates faithful chromosome segregation by pairing the sister chromatids after DNA replication until mitosis. In addition, cohesin contributes to... (Review)
Review
The cohesin complex facilitates faithful chromosome segregation by pairing the sister chromatids after DNA replication until mitosis. In addition, cohesin contributes to proficient and error-free DNA replication. Replisome progression and establishment of sister chromatid cohesion are intimately intertwined processes. Here, we review how the key factors in DNA replication and cohesion establishment cooperate in unperturbed conditions and during DNA replication stress. We discuss the detailed molecular mechanisms of cohesin recruitment and the entrapment of replicated sister chromatids at the replisome, the subsequent stabilization of sister chromatid cohesion via SMC3 acetylation, as well as the role and regulation of cohesin in the response to DNA replication stress.
Topics: Acetylation; Cell Cycle Proteins; Chromatids; Chromosomal Proteins, Non-Histone; Chromosome Segregation; DNA Replication; Mitosis; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Sister Chromatid Exchange; Cohesins
PubMed: 34943967
DOI: 10.3390/cells10123455 -
Cold Spring Harbor Perspectives in... Nov 2012During S phase, not only does DNA have to be replicated, but also newly synthesized DNA molecules have to be connected with each other. This sister chromatid cohesion is... (Review)
Review
During S phase, not only does DNA have to be replicated, but also newly synthesized DNA molecules have to be connected with each other. This sister chromatid cohesion is essential for the biorientation of chromosomes on the mitotic or meiotic spindle, and is thus an essential prerequisite for chromosome segregation. Cohesion is mediated by cohesin complexes that are thought to embrace sister chromatids as large rings. Cohesin binds to DNA dynamically before DNA replication and is converted into a stably DNA-bound form during replication. This conversion requires acetylation of cohesin, which in vertebrates leads to recruitment of sororin. Sororin antagonizes Wapl, a protein that is able to release cohesin from DNA, presumably by opening the cohesin ring. Inhibition of Wapl by sororin therefore "locks" cohesin rings on DNA and allows them to maintain cohesion for long periods of time in mammalian oocytes, possibly for months or even years.
Topics: Acetylation; Adaptor Proteins, Signal Transducing; Biological Evolution; Carrier Proteins; Cell Cycle Proteins; Chromatids; Chromosomal Proteins, Non-Histone; DNA; DNA Replication; Macromolecular Substances; Nuclear Proteins; Proto-Oncogene Proteins; Species Specificity; Cohesins
PubMed: 23043155
DOI: 10.1101/cshperspect.a011130 -
A dual-function SNF2 protein drives chromatid resolution and nascent transcripts removal in mitosis.EMBO Reports Sep 2023Mitotic chromatin is largely assumed incompatible with transcription due to changes in the transcription machinery and chromosome architecture. However, the mechanisms...
Mitotic chromatin is largely assumed incompatible with transcription due to changes in the transcription machinery and chromosome architecture. However, the mechanisms of mitotic transcriptional inactivation and their interplay with chromosome assembly remain largely unknown. By monitoring ongoing transcription in Drosophila early embryos, we reveal that eviction of nascent mRNAs from mitotic chromatin occurs after substantial chromosome compaction and is not promoted by condensin I. Instead, we show that the timely removal of transcripts from mitotic chromatin is driven by the SNF2 helicase-like protein Lodestar (Lds), identified here as a modulator of sister chromatid cohesion defects. In addition to the eviction of nascent transcripts, we uncover that Lds cooperates with Topoisomerase 2 to ensure efficient sister chromatid resolution and mitotic fidelity. We conclude that the removal of nascent transcripts upon mitotic entry is not a passive consequence of cell cycle progression and/or chromosome compaction but occurs via dedicated mechanisms with functional parallelisms to sister chromatid resolution.
Topics: Animals; Cell Cycle Proteins; Chromatids; Chromatin; DNA Topoisomerases, Type II; Drosophila; Mitosis
PubMed: 37462213
DOI: 10.15252/embr.202256463 -
Current Biology : CB Nov 2013
Topics: Anaphase; Chromatids; Chromosomal Instability; Female; Humans; Infertility; Maternal Age; Metaphase; Spindle Apparatus
PubMed: 24262830
DOI: 10.1016/j.cub.2013.08.017