Affinage

PDS5A

Sister chromatid cohesion protein PDS5 homolog A · UniProt Q29RF7

Round 2 corrected
Length
1337 aa
Mass
150.8 kDa
Annotated
2026-04-29
41 papers in source corpus 13 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PDS5A is a HEAT-repeat regulatory subunit of the cohesin complex that controls sister chromatid cohesion, chromatin loop architecture, and gene silencing by modulating cohesin dynamics on DNA. PDS5A partners with WAPL to promote cohesin removal from chromatin; after DNA replication, Sororin displaces WAPL from PDS5A to stabilize cohesion, a switch governed by ESCO1-mediated SMC3 acetylation (PMID:17113138, PMID:21111234, PMID:19907496). PDS5A functions as an acetylation-dependent brake on cohesin-mediated loop extrusion—restricting loop length, enabling CTCF boundary formation, and maintaining Polycomb-dependent transcriptional silencing of developmental genes (PMID:35710836, PMID:29217591, PMID:38071364). In oocytes, PDS5A has a cohesion-independent role in meiotic spindle assembly, recruiting USP14 to stabilize kinesin KIF5B and prevent chromosome aneuploidy (PMID:40215310).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2000 High

    The first mechanistic question was whether vertebrate cohesin had additional regulatory subunits beyond the core ring; co-purification of PDS5A with the 14S cohesin complex established it as a stoichiometric chromatin-associated cohesin partner whose dissociation parallels cohesin release at prophase.

    Evidence Biochemical co-purification and co-fractionation of PDS5 with cohesin from human cells

    PMID:11076961

    Open questions at the time
    • Whether PDS5A has a direct enzymatic or purely regulatory role was unknown
    • Mechanism of PDS5A dissociation at prophase was not defined
  2. 2006 High

    How cohesin is actively removed from chromatin was unclear; the discovery that PDS5A forms a ternary complex with WAPL and cohesin, and that WAPL requires PDS5A to promote cohesin release, established the PDS5A-WAPL axis as the cohesin unloading pathway.

    Evidence In vitro reconstitution of PDS5A-WAPL-cohesin ternary complex; reciprocal co-IP; depletion epistasis in HeLa cells, replicated across two independent labs

    PMID:17112726 PMID:17113138

    Open questions at the time
    • Whether PDS5A contacts WAPL directly or through cohesin subunits was unresolved
    • The structural basis of the PDS5A-WAPL interface was not determined
  3. 2009 High

    The link between cohesin acetylation and chromatin dynamics was unclear; showing that PDS5A-WAPL promotes a hyperstable cohesin-chromatin interaction on unacetylated cohesin that impedes replication fork progression established SMC3 acetylation as a switch that counteracts PDS5A-WAPL-mediated chromatin retention.

    Evidence Single-molecule DNA fiber analysis with siRNA knockdown of PDS5A/WAPL and ESCO1/ESCO2 in human cells

    PMID:19907496

    Open questions at the time
    • Whether acetylation alters PDS5A binding affinity for cohesin directly was not tested biochemically
    • Role of HDAC-mediated reversal was not addressed
  4. 2010 High

    How cohesion is stabilized after S-phase despite the presence of PDS5A-WAPL was a central question; the finding that Sororin competitively displaces WAPL from PDS5A in an acetylation-dependent manner explained the molecular switch from cohesin removal to cohesion establishment.

    Evidence Reciprocal co-IP, competition biochemistry, and siRNA epistasis in human cells

    PMID:21111234

    Open questions at the time
    • Structural basis of the Sororin-PDS5A versus WAPL-PDS5A competition was unknown
    • Whether PDS5A and PDS5B are equivalently regulated by Sororin was not tested
  5. 2017 High

    Whether cohesin loop extrusion is unlimited or actively restrained was unknown; acute depletion of PDS5 proteins showed they are essential for CTCF boundary function and loop length control, with their loss producing extended loops and axial 'vermicelli' chromosome morphology.

    Evidence Auxin-inducible degron depletion of PDS5A/B; Hi-C, ChIP-seq, and live-cell imaging in human cells

    PMID:29217591

    Open questions at the time
    • The mechanism by which PDS5 pauses cohesin at CTCF sites was not defined
    • Individual contributions of PDS5A versus PDS5B were not fully separated
  6. 2022 High

    Whether SMC3 acetylation regulates loop extrusion independently of its role in preventing WAPL-mediated release was unresolved; demonstrating that ESCO1-mediated acetylation promotes PDS5A interaction with cohesin to create a 'brake' that limits loop extension established a second, mechanistically distinct function for the acetylation-PDS5A axis.

    Evidence Auxin-inducible degron depletion of ESCO1/HDAC8; Hi-C, ChIP-seq, and co-IP in human cells

    PMID:35710836

    Open questions at the time
    • Whether PDS5A directly contacts acetylated SMC3 or recognizes a conformational change was not resolved structurally
    • HDAC8-independent deacetylation pathways were not excluded
  7. 2023 High

    Whether cohesin regulation by PDS5A influences gene silencing beyond loop architecture was open; deletion of PDS5A in mouse ESCs disrupted ultra-long Polycomb loops and derepressed PRC1/PRC2 target genes without loss of Polycomb histone marks, linking PDS5A-dependent genome topology to transcriptional repression.

    Evidence CRISPR deletion of PDS5A in mouse ESCs; Hi-C, RNA-seq, and ChIP-seq for Polycomb marks

    PMID:38071364

    Open questions at the time
    • Whether PDS5B compensates partially for PDS5A loss at Polycomb targets was not fully resolved
    • Direct physical interaction between PDS5A and Polycomb complexes was not tested
  8. 2025 High

    Whether PDS5A has cohesion-independent functions was unexplored; showing that PDS5A localizes to meiotic spindle fibers and recruits USP14 to deubiquitinate and stabilize kinesin KIF5B revealed a non-canonical role in spindle assembly and chromosome segregation fidelity in oocytes.

    Evidence Morpholino depletion and conditional genetic ablation in mouse oocytes; immunofluorescence, co-IP, and deubiquitination assay

    PMID:40215310

    Open questions at the time
    • Whether this spindle function operates in mitosis or only in meiosis is unknown
    • The domain of PDS5A that contacts USP14 was not mapped
  9. 2025 Medium

    The mechanism by which PDS5 halts loop extrusion was biochemically undefined; in vitro single-molecule imaging demonstrated that PDS5 stops cohesin-driven extrusion by facilitating NIPBL dissociation from the cohesin complex, and simulations showed this limits cohesin velocity and residence time to enable compartment separation.

    Evidence Single-molecule loop extrusion reconstitution; Hi-C validation; polymer simulations (preprint)

    PMID:bio_10.1101_2025.08.30.673243

    Open questions at the time
    • Awaits peer review
    • Whether NIPBL dissociation kinetics differ between PDS5A and PDS5B was not tested
    • Structural basis of NIPBL displacement by PDS5 is unknown
  10. 2026 Medium

    Whether PDS5A and PDS5B are functionally redundant in vivo was uncertain; double depletion in medaka embryos revealed cooperative roles in constraining long-range chromatin interactions during embryogenesis, with single depletions causing only modest changes.

    Evidence Morpholino depletion in medaka embryos; Hi-C and RNA-seq

    PMID:41994921

    Open questions at the time
    • Single species and single lab; cross-species confirmation needed
    • Whether developmental phenotypes are entirely genome-architecture-dependent or reflect other PDS5 functions is unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis of PDS5A interactions with WAPL, Sororin, and NIPBL at atomic resolution; whether PDS5A and PDS5B have paralog-specific chromatin targets or regulatory partners; and how PDS5A's spindle function is coordinated with its canonical cohesin role during cell division.
  • No high-resolution structure of PDS5A in complex with cohesin or WAPL
  • Paralog-specific mechanisms remain poorly defined
  • Regulation of the switch between cohesin-associated and spindle-associated PDS5A pools is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6 GO:0060090 molecular adaptor activity 2
Localization
GO:0005694 chromosome 4 GO:0005654 nucleoplasm 3 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1640170 Cell Cycle 4 R-HSA-4839726 Chromatin organization 3 R-HSA-73894 DNA Repair 1 R-HSA-74160 Gene expression (Transcription) 1
Partners
CDCA5CTCFKIF5BRAD21SMC1ASMC3USP14WAPL
Complex memberships
PDS5A-WAPL releasing complexcohesin complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 PDS5A (as PDS5) was identified as a protein that interacts with vertebrate cohesin complexes (containing SMC1, SMC3, SCC1, and SA1 or SA2 subunits). PDS5 co-purifies with 14S cohesin and is chromatin-associated until prophase, when it becomes soluble along with cohesin. Biochemical purification of cohesin complexes from human cells; co-purification/co-fractionation The Journal of cell biology High 11076961
2006 PDS5A interacts with WAPL (Wings apart-like protein), and together they form a ternary complex with cohesin regulatory subunits. WAPL promotes release of cohesin from chromosomes through direct interaction with PDS5 binding partners, establishing PDS5 as a cofactor in the WAPL-mediated cohesin removal pathway. In vitro reconstitution of ternary complex; co-immunoprecipitation; depletion experiments in HeLa cells Cell / Current biology : CB High 17112726 17113138
2009 PDS5A acts as a cofactor that mediates cohesin's hyperstable interaction with chromatin in the absence of SMC3 acetylation. Removal of PDS5A (or WAPL) rescued slow replication fork progression caused by loss of cohesin acetyltransferases ESCO1/ESCO2, establishing that PDS5A-WAPL interaction with unacetylated cohesin impedes replication fork velocity. Single-molecule DNA fiber analysis; siRNA knockdown of PDS5A and WAPL in human cells; genetic epistasis with ESCO1/ESCO2 depletion Nature High 19907496
2010 Sororin displaces WAPL from its binding partner PDS5, thereby antagonizing WAPL's ability to dissociate cohesin from DNA. DNA replication and cohesin acetylation promote Sororin binding to cohesin (specifically to PDS5), and in the absence of WAPL, Sororin becomes dispensable for cohesion. Co-immunoprecipitation; siRNA depletion epistasis; biochemical competition assay Cell High 21111234
2017 PDS5 proteins (PDS5A and PDS5B) are required for CTCF boundary function and control the length of cohesin-mediated chromatin loops. In the absence of WAPL and PDS5 proteins, cohesin forms extended loops, accumulates in axial chromosomal 'vermicelli' positions, and condenses chromosomes. PDS5 proteins are required for cohesin to pause at CTCF sites during loop extrusion. Auxin-inducible degron depletion; Hi-C; ChIP-seq; live-cell imaging in human cells The EMBO journal High 29217591
2022 The cohesin acetylation cycle controls chromatin loop length through a PDS5A-dependent brake mechanism. ESCO1-mediated acetylation of SMC3 promotes cohesin interaction with PDS5A, creating a paused state that restricts loop extension and limits CTCF-anchored stripe length. HDAC8-mediated deacetylation reverses this, promoting loop extension. This PDS5A brake function is distinct from the canonical role of acetylation in protecting against WAPL-mediated DNA release. Auxin-inducible degron depletion of ESCO1/HDAC8; Hi-C; ChIP-seq; co-immunoprecipitation in human cells Nature structural & molecular biology High 35710836
2020 PDS5A and PDS5B display non-redundant functions in mitosis: loss of either alone increases SMC3 acetylation in perturbed cell cycle, while loss of both severely impairs SMC3 acetylation. PDS5A/B depletion leads to DNA damage, activation of ATR-Chk1-dependent SAC, stabilization of WAPL on chromatin, and induction of pro-apoptotic markers. Depletion of Chk1 rescued S-phase delay but increased mitotic catastrophe. siRNA knockdown; western blot for Chk1 phosphorylation and SMC3 acetylation; FACS cell cycle analysis; MAD2 localization by immunofluorescence Frontiers in cell and developmental biology Medium 32760717
2023 PDS5A deletion impairs cohesin unloading and disrupts ultra-long Polycomb loops, causing derepression of a subset of PRC1/PRC2 target genes without loss of Polycomb chromatin domains. PDS5A links Polycomb-mediated transcriptional silencing to 3D genome organization by maintaining cohesin-dependent genome architecture required for Polycomb loop formation. CRISPR screen in mouse ESCs; PDS5A deletion; Hi-C; RNA-seq; ChIP-seq for Polycomb marks Nature communications High 38071364
2025 Pds5A plays a non-canonical role in meiotic spindle assembly in oocytes, independent of its cohesion function. Pds5A localizes to spindle fibers at metaphase I and II; its depletion causes spindle organization defects and chromosome aneuploidy. Mechanistically, Pds5A recruits deubiquitinase USP14 to the spindle apparatus to stabilize kinesin KIF5B, thereby regulating spindle elongation. Morpholino depletion; conditional genetic ablation in mouse oocytes; immunofluorescence; co-immunoprecipitation; deubiquitination assay Science advances High 40215310
2026 Pds5a and Pds5b act cooperatively to constrain cohesin-mediated long-range chromatin interactions during vertebrate embryogenesis. Single depletion of either paralog causes only modest 3D genome changes, but double depletion causes pronounced architectural alterations including increased long-range contacts and de novo extended chromatin loops. Morpholino depletion in medaka embryos; Hi-C; RNA-seq; developmental transcriptome analysis Development, growth & differentiation Medium 41994921
2026 PDS5A and TOP2B cooperate for their recruitment to CTCF-bound chromatin. Catalytically active TOP2B increases PDS5A chromatin occupancy genome-wide. A novel PDS5A-interaction region in the CTCF N-terminal domain (aa 95-116) is required for the CTCF-PDS5A-TOP2B interaction in vitro and for TOP2B-mediated enrichment of PDS5A chromatin occupancy in vivo. Loss of this interaction reduces chromatin loop number and dysregulates gene expression. PDS5A mediates sensitivity to TOP2 inhibitor drugs in glioma cells. Co-immunoprecipitation; CTCF truncation mutants; ChIP-seq; inducible PDS5A knockdown; drug sensitivity assays in glioma cells bioRxivpreprint Medium 41959374
2025 PDS5 proteins stop cohesin-mediated loop extrusion by facilitating the dissociation of NIPBL from cohesin, as demonstrated by in vitro single-molecule imaging. This function is required for CTCF boundary establishment in cells, and in silico modeling shows PDS5 proteins enable compartment separation by limiting cohesin velocity and chromatin-residence time. In vitro single-molecule imaging of loop extrusion; Hi-C; polymer simulation modeling bioRxivpreprint Medium bio_10.1101_2025.08.30.673243

Source papers

Stage 0 corpus · 41 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2017 Topologically associating domains and chromatin loops depend on cohesin and are regulated by CTCF, WAPL, and PDS5 proteins. The EMBO journal 615 29217591
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
2006 Wapl controls the dynamic association of cohesin with chromatin. Cell 498 17113138
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2000 Characterization of vertebrate cohesin complexes and their regulation in prophase. The Journal of cell biology 358 11076961
2006 Human Wapl is a cohesin-binding protein that promotes sister-chromatid resolution in mitotic prophase. Current biology : CB 356 17112726
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2010 Sororin mediates sister chromatid cohesion by antagonizing Wapl. Cell 305 21111234
2011 Mapping a dynamic innate immunity protein interaction network regulating type I interferon production. Immunity 286 21903422
2011 A directed protein interaction network for investigating intracellular signal transduction. Science signaling 258 21900206
2013 Why do cellular proteins linked to K63-polyubiquitin chains not associate with proteasomes? The EMBO journal 213 23314748
2006 Human Scc4 is required for cohesin binding to chromatin, sister-chromatid cohesion, and mitotic progression. Current biology : CB 209 16682347
2009 Cohesin acetylation speeds the replication fork. Nature 208 19907496
2013 PRP19 transforms into a sensor of RPA-ssDNA after DNA damage and drives ATR activation via a ubiquitin-mediated circuitry. Molecular cell 204 24332808
2005 Sororin, a substrate of the anaphase-promoting complex, is required for sister chromatid cohesion in vertebrates. Molecular cell 202 15837422
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2020 Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions. Nature cell biology 194 32203420
2022 The cohesin acetylation cycle controls chromatin loop length through a PDS5A brake mechanism. Nature structural & molecular biology 50 35710836
2021 PDS5A and PDS5B in Cohesin Function and Human Disease. International journal of molecular sciences 33 34070827
2004 SCC-112, a novel cell cycle-regulated molecule, exhibits reduced expression in human renal carcinomas. Gene 20 15019998
2007 SCC-112 gene is involved in tumor progression and promotes the cell proliferation in G2/M phase. Journal of cancer research and clinical oncology 14 17846787
2023 Loss of cohesin regulator PDS5A reveals repressive role of Polycomb loops. Nature communications 12 38071364
2022 Knockdown of CDCA5 suppresses malignant progression of breast cancer cells by regulating PDS5A. Molecular medicine reports 6 35506437
2020 Pds5A and Pds5B Display Non-redundant Functions in Mitosis and Their Loss Triggers Chk1 Activation. Frontiers in cell and developmental biology 6 32760717
2011 HIV-1 infection suppresses expression of host cell cycle-associated gene PDS5A. Intervirology 3 21865657
2025 The cohesin-associated protein Pds5A governs the meiotic spindle assembly via deubiquitination of Kif5B in oocytes. Science advances 2 40215310
2026 PDS5A and TOP2B cooperate for chromatin recruitment via CTCF. bioRxiv : the preprint server for biology 0 41959374
2026 Cooperative Roles of Pds5a and Pds5b Constrain Long-Range Chromatin Interactions in Vertebrate Embryos. Development, growth & differentiation 0 41994921