Affinage

PDS5A

Sister chromatid cohesion protein PDS5 homolog A · UniProt Q29RF7

Length
1337 aa
Mass
150.8 kDa
Annotated
2026-06-10
11 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PDS5A is a regulatory subunit of the cohesin complex that constrains cohesin-mediated DNA loop extrusion to shape three-dimensional genome architecture [PMID:35710836, PMID:bio_10.1101_2025.08.30.673243]. Mechanistically, it acts as a NIPBL-dissociation factor that limits the cohesin–NIPBL lifetime, halting loop extrusion and enabling establishment of CTCF boundaries and chromatin compartmentalization [PMID:bio_10.1101_2025.08.30.673243]. PDS5A binding to cohesin is promoted by ESCO1-mediated SMC3 acetylation, generating a 'braked' state that pauses loop enlargement, whereas HDAC8-dependent deacetylation releases this brake to restart extrusion—a loop-length control distinct from the canonical WAPL-mediated DNA release pathway (PMID:35710836). PDS5A also supports cohesin unloading, and its loss produces aberrant cohesin activity, ectopic insulation, and disruption of ultra-long Polycomb loops required for robust PRC1/PRC2 target silencing (PMID:38071364). PDS5A and its paralog PDS5B have overlapping roles in facilitating SMC3 acetylation while retaining non-redundant functions in cohesin removal (PMID:32760717), and act cooperatively in vivo to constrain loop extrusion during development (PMID:41994921). Beyond chromatin, PDS5A has a cohesion-independent role in meiotic spindle assembly, localizing to spindle fibers in mouse oocytes where it recruits the deubiquitinase USP14 to stabilize KIF5B and regulate spindle elongation (PMID:40215310).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2007 Low

    An early attempt to assign PDS5A a function linked it to a p63-dependent proliferative role, raising the possibility of activity outside cohesin biology.

    Evidence Co-immunoprecipitation, overexpression/knockdown, proliferation and cell-cycle assays in human cells

    PMID:17846787

    Open questions at the time
    • Single Co-IP without reciprocal validation or in vitro confirmation
    • No connection drawn to cohesin or loop architecture
    • p63 link not corroborated by later mechanistic work
  2. 2020 Medium

    To resolve whether PDS5A and PDS5B are redundant in cohesin regulation, paralog depletion experiments showed they cooperate in SMC3 acetylation yet retain non-redundant roles in cohesin removal and checkpoint control.

    Evidence siRNA single and co-depletion, acetyl-SMC3 western blot, WAPL/MAD2 immunofluorescence, Chk1-inhibitor rescue in human cells

    PMID:32760717

    Open questions at the time
    • Mechanism of how PDS5A facilitates SMC3 acetylation not defined
    • Performed in perturbed cell cycle, leaving steady-state role unclear
    • Does not address loop-level architectural consequences
  3. 2022 High

    The question of how acetylation cycles control loop length was answered by showing ESCO1-driven SMC3 acetylation promotes a PDS5A-bound braked state that pauses extrusion, reversibly released by HDAC8.

    Evidence Hi-C, ChIP-seq, auxin-inducible degron depletion of ESCO1/HDAC8 in human cells

    PMID:35710836

    Open questions at the time
    • Structural basis of the braked PDS5A–cohesin state not resolved
    • Relationship between braking and NIPBL dissociation not yet connected
    • Quantitative kinetics of pause/restart unmeasured in vivo
  4. 2023 High

    To place PDS5A in gene-regulatory architecture, its deletion was shown to impair cohesin unloading and disrupt ultra-long Polycomb loops, defining a role in maintaining genome organization needed for Polycomb silencing.

    Evidence CRISPR screen, PDS5A deletion, Hi-C, RNA-seq, ChIP-seq in mouse ESCs

    PMID:38071364

    Open questions at the time
    • How loss of unloading mechanistically derepresses only a subset of targets unclear
    • Direct biochemical link between PDS5A and Polycomb machinery not established
    • Polycomb chromatin domains persist, decoupling silencing from domain identity
  5. 2025 High

    The biochemical mechanism by which PDS5 stops loop extrusion was directly resolved: PDS5 facilitates NIPBL dissociation from cohesin, limiting cohesin–NIPBL lifetime and enabling CTCF boundary establishment.

    Evidence In vitro single-molecule imaging of loop extrusion, Hi-C, polymer modelling (preprint)

    PMID:bio_10.1101_2025.08.30.673243

    Open questions at the time
    • Awaits peer review
    • How NIPBL dissociation integrates with the acetylation-dependent braked state not unified
    • Paralog-specific contributions in the reconstituted system not separated
  6. 2025 Medium

    PDS5A was assigned a discrete role in CTCF boundary mechanics, tuning CTCF's conformational ensemble before cohesin engagement and reinforcing loop-anchor stability after binding.

    Evidence Single-molecule imaging of CTCF dynamics and in vitro CTCF–cohesin–PDS5A reconstitution with mechanical stability assays (preprint)

    PMID:bio_10.1101_2025.11.25.690553

    Open questions at the time
    • Preprint, single lab, not independently replicated
    • In vivo relevance of CTCF conformational tuning not demonstrated
    • Structural detail of PDS5A–CTCF contact undefined
  7. 2025 High

    A cohesion-independent function emerged: in oocytes PDS5A localizes to the meiotic spindle and recruits USP14 to deubiquitinate and stabilize KIF5B, controlling spindle elongation.

    Evidence Morpholino depletion plus genetic knockout in mouse oocytes, immunofluorescence, Co-IP, ubiquitination assay

    PMID:40215310

    Open questions at the time
    • How PDS5A is targeted to the spindle is unknown
    • Whether this function generalizes beyond meiotic oocytes unclear
    • Structural basis of PDS5A–USP14 interaction undefined
  8. 2026 Medium

    PDS5A's partnership with the topoisomerase TOP2B at CTCF boundaries was defined, with a CTCF N-terminal region (aa 95–116) required for the CTCF–PDS5A–TOP2B interaction.

    Evidence In vitro binding with CTCF deletion mutants, ChIP-seq, inducible PDS5A knockdown, Hi-C (preprint)

    PMID:41959374

    Open questions at the time
    • Preprint, not peer reviewed
    • Functional consequence of TOP2B catalytic activity on loop dynamics not fully resolved
    • How this interaction relates to the braked/NIPBL-dissociation mechanisms unclear
  9. 2026 Medium

    In vivo developmental relevance was confirmed by showing Pds5a and Pds5b cooperatively constrain loop extrusion in medaka embryos, with phenotypes only on double depletion.

    Evidence Morpholino depletion in medaka embryos, in situ Hi-C, RNA-seq

    PMID:41994921

    Open questions at the time
    • Single vs double depletion does not separate paralog-specific roles
    • Developmental phenotypes downstream of loop changes not characterized
    • Single lab in one model organism

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the distinct PDS5A activities—NIPBL dissociation, acetylation-dependent braking, cohesin unloading, CTCF/TOP2B boundary cooperation, and meiotic spindle regulation—are coordinated within a unified molecular framework remains unresolved.
  • No structural model integrating the braked, NIPBL-dissociating, and CTCF-stabilizing states
  • Switch between chromatin and spindle functions uncharacterized
  • Quantitative partitioning of PDS5A vs PDS5B in each activity undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005694 chromosome 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-4839726 Chromatin organization 2 R-HSA-1640170 Cell Cycle 1
Partners
CTCFKIF5BNIPBLPDS5BTOP2BUSP14WAPL
Complex memberships
cohesin complex

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2022 Cohesin acetylation by ESCO1 restricts chromatin loop length and architectural stripes by promoting PDS5A binding to cohesin, which acts as a brake enabling pausing and restart of loop enlargement; HDAC8-mediated deacetylation promotes loop extension by releasing this PDS5A-bound braked state. This role in loop-length control is distinct from the canonical WAPL-mediated DNA release pathway. Hi-C, ChIP-seq, auxin-inducible degron depletion of ESCO1/HDAC8, functional genomics in human cells Nature structural & molecular biology High 35710836
2023 PDS5A loss impairs cohesin unloading, causing aberrant cohesin activity that generates ectopic insulation sites and disrupts ultra-long Polycomb loops, which are required for robust silencing of a subset of PRC1/PRC2 target genes; derepression occurs without loss of Polycomb chromatin domains, placing PDS5A as a cohesin unloading regulator whose activity maintains genome architecture needed for Polycomb gene silencing. CRISPR screen in mouse ESCs, PDS5A deletion, Hi-C, RNA-seq, ChIP-seq Nature communications High 38071364
2020 Depletion of Pds5A or Pds5B individually increased SMC3 acetylation in perturbed cell cycle, whereas co-depletion of both severely impaired SMC3 acetylation, demonstrating overlapping roles in facilitating SMC3 acetylation. Additionally, Pds5A/B loss stabilized WAPL on chromatin and activated the spindle assembly checkpoint via an ATR-Chk1-dependent mechanism, revealing non-redundant functions in cohesin removal. siRNA knockdown, western blot for acetyl-SMC3, immunofluorescence for MAD2/WAPL, flow cytometry, Chk1 inhibitor rescue Frontiers in cell and developmental biology Medium 32760717
2025 Pds5A localizes to spindle fibers in mouse oocytes at metaphase I and II and plays a non-canonical, cohesion-independent role in meiotic spindle assembly. Mechanistically, Pds5A recruits the deubiquitinase USP14 to the spindle apparatus, which stabilizes kinesin family member KIF5B by deubiquitination, thereby regulating spindle elongation. Morpholino depletion, genetic knockout in mouse oocytes, immunofluorescence, co-immunoprecipitation, ubiquitination assay Science advances High 40215310
2007 SCC-112/PDS5A protein was found to interact with p63 by co-immunoprecipitation, and overexpression of SCC-112 up-regulated p63 expression, promoting cell proliferation in G2/M phase. Co-immunoprecipitation, overexpression/siRNA knockdown, MTT proliferation assay, FACS cell cycle analysis Journal of cancer research and clinical oncology Low 17846787
2026 PDS5A interacts with TOP2B and CTCF; a novel CTCF N-terminal region (amino acids 95–116) is required for the CTCF–PDS5A–TOP2B interaction in vitro and for TOP2B-mediated enrichment of PDS5A chromatin occupancy in vivo. Catalytically active TOP2B increases PDS5A occupancy genome-wide, and PDS5A knockdown reduces TOP2B chromatin occupancy and alters gene expression. In vitro binding assay with CTCF deletion mutants, ChIP-seq, inducible PDS5A knockdown, chromatin loop analysis by Hi-C bioRxivpreprint Medium 41959374
2025 PDS5 proteins stop cohesin-mediated loop extrusion by facilitating dissociation of NIPBL from cohesin, as demonstrated by in vitro single-molecule imaging; this mechanism limits cohesin-NIPBL lifetime and is required for establishment of CTCF boundaries and maintenance of chromatin compartmentalization. In vitro single-molecule imaging, Hi-C, in silico polymer modelling bioRxivpreprint High bio_10.1101_2025.08.30.673243
2025 PDS5A tunes the conformational ensemble of CTCF before cohesin engagement, influencing the probability that cohesin stalls at CTCF boundaries; upon cohesin binding, PDS5A enhances the mechanical stability of loop anchors, reinforcing orientation-dependent boundaries. Single-molecule imaging of CTCF conformational dynamics, in vitro cohesin–CTCF–PDS5A reconstitution, mechanical stability assays bioRxivpreprint Medium bio_10.1101_2025.11.25.690553
2026 In medaka embryos, simultaneous depletion of both Pds5a and Pds5b, but not single depletion, caused pronounced increases in long-range chromatin contacts and de novo formation of extended chromatin loops by Hi-C, demonstrating that Pds5a and Pds5b act cooperatively to constrain cohesin-mediated loop extrusion in vivo during development. Morpholino-mediated depletion in medaka embryos, in situ Hi-C, RNA-seq Development, growth & differentiation Medium 41994921

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 The cohesin acetylation cycle controls chromatin loop length through a PDS5A brake mechanism. Nature structural & molecular biology 59 35710836
2021 PDS5A and PDS5B in Cohesin Function and Human Disease. International journal of molecular sciences 35 34070827
2004 SCC-112, a novel cell cycle-regulated molecule, exhibits reduced expression in human renal carcinomas. Gene 20 15019998
2023 Loss of cohesin regulator PDS5A reveals repressive role of Polycomb loops. Nature communications 14 38071364
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
2020 Pds5A and Pds5B Display Non-redundant Functions in Mitosis and Their Loss Triggers Chk1 Activation. Frontiers in cell and developmental biology 7 32760717
2022 Knockdown of CDCA5 suppresses malignant progression of breast cancer cells by regulating PDS5A. Molecular medicine reports 6 35506437
2025 The cohesin-associated protein Pds5A governs the meiotic spindle assembly via deubiquitination of Kif5B in oocytes. Science advances 3 40215310
2011 HIV-1 infection suppresses expression of host cell cycle-associated gene PDS5A. Intervirology 3 21865657
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

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