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PDS5A and PDS5B in Cohesin Function and Human Disease.

ABSTRACT: Precocious dissociation of sisters 5 (PDS5) is an associate protein of cohesin that is conserved from yeast to humans. It acts as a regulator of the cohesin complex and plays important roles in various cellular processes, such as sister chromatid cohesion, DNA damage repair, gene transcription, and DNA replication. Vertebrates have two paralogs of PDS5, PDS5A and PDS5B, which have redundant and unique roles in regulating cohesin functions. Herein, we discuss the molecular characteristics and functions of PDS5, as well as the effects of its mutations in the development of diseases and their relevance for novel therapeutic strategies.

SUBMITTER: Zhang N

PROVIDER: S-EPMC8198109 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Topology and structure of an engineered human cohesin complex bound to Pds5B.

Project description:The cohesin subunits Smc1, Smc3 and Scc1 form large tripartite rings which mediate sister chromatid cohesion and chromatin structure. These are thought to entrap DNA with the help of the associated proteins SA1/2 and Pds5A/B. Structural information is available for parts of cohesin, but analyses of entire cohesin complexes are limited by their flexibility. Here we generated a more rigid 'bonsai' cohesin by truncating the coiled coils of Smc1 and Smc3 and used single-particle electron microscopy, chemical crosslinking-mass spectrometry and in silico modelling to generate three-dimensional models of cohesin bound to Pds5B. The HEAT-repeat protein Pds5B forms a curved structure around the nucleotide-binding domains of Smc1 and Smc3 and bridges the Smc3-Scc1 and SA1-Scc1 interfaces. These results indicate that Pds5B forms an integral part of the cohesin ring by contacting all other cohesin subunits, a property that may reflect the complex role of Pds5 proteins in controlling cohesin-DNA interactions.

| S-EPMC4996973 | biostudies-literature

PDS5A and PDS5B differentially affect gene expression without altering cohesin localization across the genome.

Project description:BackgroundCohesin is an important structural regulator of the genome, regulating both three-dimensional genome organization and gene expression. The core cohesin trimer interacts with various HEAT repeat accessory subunits, yielding cohesin complexes of distinct compositions and potentially distinct functions. The roles of the two mutually exclusive HEAT repeat subunits PDS5A and PDS5B are not well understood.ResultsHere, we determine that PDS5A and PDS5B have highly similar localization patterns across the mouse embryonic stem cell (mESC) genome and they show a strong overlap with other cohesin HEAT repeat accessory subunits, STAG1 and STAG2. Using CRISPR/Cas9 genome editing to generate individual stable knockout lines for PDS5A and PDS5B, we find that loss of one PDS5 subunit does not alter the distribution of the other PDS5 subunit, nor the core cohesin complex. Both PDS5A and PDS5B are required for proper gene expression, yet they display only partially overlapping effects on gene targets. Remarkably, gene expression following dual depletion of the PDS5 HEAT repeat proteins does not completely overlap the gene expression changes caused by dual depletion of the STAG HEAT repeat proteins, despite the overlapping genomic distribution of all four proteins. Furthermore, dual loss of PDS5A and PDS5B decreases cohesin association with NIPBL and WAPL, reduces SMC3 acetylation, and does not alter overall levels of cohesin on the genome.ConclusionsThis work reveals the importance of PDS5A and PDS5B for proper cohesin function. Loss of either subunit has little effect on cohesin localization across the genome yet PDS5A and PDS5B are differentially required for gene expression.

| S-EPMC9392266 | biostudies-literature

Cohesin and human disease.

Project description:Cornelia de Lange syndrome (CdLS) is a dominant multisystem disorder caused by a disruption of cohesin function. The cohesin ring complex is composed of four protein subunits and more than 25 additional proteins involved in its regulation. The discovery that this complex also has a fundamental role in long-range regulation of transcription in Drosophila has shed light on the mechanism likely responsible for its role in development. In addition to the three cohesin proteins involved in CdLS, a second multisystem, recessively inherited, developmental disorder, Roberts-SC phocomelia, is caused by mutations in another regulator of the cohesin complex, ESCO2. Here we review the phenotypes of these disorders, collectively termed cohesinopathies, as well as the mechanism by which cohesin disruption likely causes these diseases.

| S-EPMC4894839 | biostudies-literature

The Mouse Cohesin-Associated Protein PDS5B Is Expressed in Testicular Cells and Is Associated with the Meiotic Chromosome Axes.

Project description:During the first meiotic prophase, the cohesin complex is localized to the chromosome axis and contributes to chromosome organization, pairing, synapsis, and recombination. The PDS5 protein, an accessory factor of the cohesin complex, is known to be a component of meiotic chromosome cores in fungi and to be implicated in meiotic chromosome structure and function. We found by immunoblotting experiments that a mammalian PDS5 protein, PDS5B, is abundantly expressed in mouse testis compared to other tissues. Immunofluorescence labeling experiments revealed that PDS5B is highly expressed in spermatogonia and that most PDS5B is depleted from chromatin as cells enter meiosis. During the first meiotic prophase, PDS5B associates with the axial cores of chromosomes. The axial association of PDS5B was observed also in the absence of synaptonemal complex proteins, such as SYCP1 and SYCP3, suggesting that PDS5B is an integral part of the chromosome axis as defined by the cohesin complex. These results suggest that PDS5B modulates cohesin functions in spermatocytes as well as in spermatogonia, contributing to meiotic chromosome structure and function.

| S-EPMC3966231 | biostudies-literature

Meiotic Cohesin and Variants Associated With Human Reproductive Aging and Disease.

Project description:Successful human reproduction relies on the well-orchestrated development of competent gametes through the process of meiosis. The loading of cohesin, a multi-protein complex, is a key event in the initiation of mammalian meiosis. Establishment of sister chromatid cohesion via cohesin rings is essential for ensuring homologous recombination-mediated DNA repair and future proper chromosome segregation. Cohesin proteins loaded during female fetal life are not replenished over time, and therefore are a potential etiology of age-related aneuploidy in oocytes resulting in decreased fecundity and increased infertility and miscarriage rates with advancing maternal age. Herein, we provide a brief overview of meiotic cohesin and summarize the human genetic studies which have identified genetic variants of cohesin proteins and the associated reproductive phenotypes including primary ovarian insufficiency, trisomy in offspring, and non-obstructive azoospermia. The association of cohesion defects with cancer predisposition and potential impact on aging are also described. Expansion of genetic testing within clinical medicine, with a focus on cohesin protein-related genes, may provide additional insight to previously unknown etiologies of disorders contributing to gamete exhaustion in females, and infertility and reproductive aging in both men and women.

| S-EPMC8365356 | biostudies-literature

FACT mediates cohesin function on chromatin.

Project description:Cohesin is a regulator of genome architecture with roles in sister chromatid cohesion and chromosome compaction. The recruitment and mobility of cohesin complexes on DNA is restricted by nucleosomes. Here, we show that the role of cohesin in chromosome organization requires the histone chaperone FACT ('facilitates chromatin transcription') in Saccharomyces cerevisiae. We find that FACT interacts directly with cohesin, and is dynamically required for its localization on chromatin. Depletion of FACT in metaphase cells prevents cohesin accumulation at pericentric regions and causes reduced binding on chromosome arms. Using the Hi-C technique, we show that cohesin-dependent TAD (topological associated domain)-like structures in G1 and metaphase chromosomes are reduced in the absence of FACT. Sister chromatid cohesion is intact in FACT-depleted cells, although chromosome segregation failure is observed. Our data show that FACT contributes to the formation of cohesin-dependent TADs, thus uncovering a new role for this complex in nuclear organization during interphase and mitotic chromosome folding.

| S-EPMC6779571 | biostudies-literature

PDS5A and PDS5B differentially affect gene expression without altering cohesin localization across the genome

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-08-21 | GSE199356 | GEO

The human Shu complex functions with PDS5B and SPIDR to promote homologous recombination.

Project description:RAD51 plays a central role in homologous recombination during double-strand break repair and in replication fork dynamics. Misregulation of RAD51 is associated with genetic instability and cancer. RAD51 is regulated by many accessory proteins including the highly conserved Shu complex. Here, we report the function of the human Shu complex during replication to regulate RAD51 recruitment to DNA repair foci and, secondly, during replication fork restart following replication fork stalling. Deletion of the Shu complex members, SWS1 and SWSAP1, using CRISPR/Cas9, renders cells specifically sensitive to the replication fork stalling and collapse caused by methyl methanesulfonate and mitomycin C exposure, a delayed and reduced RAD51 response, and fewer sister chromatid exchanges. Our additional analysis identified SPIDR and PDS5B as novel Shu complex interacting partners and genetically function in the same pathway upon DNA damage. Collectively, our study uncovers a protein complex, which consists of SWS1, SWSAP1, SPIDR and PDS5B, involved in DNA repair and provides insight into Shu complex function and composition.

| S-EPMC6821187 | biostudies-literature

PDS5A and PDS5B differentially affect gene expression without altering cohesin localization across the genome [ChIP-seq]

Project description:Purpose: Cohesin is an important structural regulator of the genome. Whether cohesin HEAT repeat accessory proteins PDS5A and PDS5B differentially contribute to cohesin function remains unclear. The purpose of this study is to interrogate how PDS5A and PDS5B affect cohesin localization and gene expression in mouse embronic stem cells (mESCs) Method: Genome wide binding patterns of PDS5A, PDS5B, and cohesin in wildtype cells as well as in PDS5 CRISPR/Cas9 genome edited knockout cells were assessed via chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq). The redundancy of the PDS5 subunits was addressed by using siRNA against PDS5B in a PDS5A-knockout background.

2022-08-21 | GSE199354 | GEO

PDS5A and PDS5B differentially affect gene expression without altering cohesin localization across the genome [RNA-seq]

Project description:Purpose: Cohesin is an important structural regulator of the genome. Whether cohesin HEAT repeat accessory proteins PDS5A and PDS5B differentially contribute to cohesin function remains unclear. The purpose of this study is to interrogate how PDS5A and PDS5B affect cohesin localization and gene expression in mouse embronic stem cells (mESCs) Method: The role of PDS5A and PDS5B in gene regulation was assessed by performing RNA-seq in wildtype and CRISPR-Cas9 genome edited PDS5 knockout mouse embryonic stem cells (mESCs). The redundancy of the PDS5s was addressed by using siRNA against PDS5B in a PDS5A-knockout background. Whether PDS5 and STAG proteins have selective roles in gene expression was addressed by using siRNA against STAG1 and STAG2 in a PDS5A-KO background

2022-08-21 | GSE199255 | GEO

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