Affinage

WAPL

Wings apart-like protein homolog · UniProt Q7Z5K2

Length
1190 aa
Mass
132.9 kDa
Annotated
2026-06-11
100 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

WAPL is the principal cohesin release factor that controls the residence time of the cohesin ring on chromatin, thereby setting the length of chromatin loops and the position of TAD boundaries genome-wide (PMID:29217591). Acting together with PDS5, WAPL opens the Smc3-Scc1 exit gate of cohesin in a manner aided by ATP hydrolysis, and PDS5 prolongs the open state to release DNA (PMID:28220956); the Wapl-Pds5 complex also suppresses the intrinsic ATPase-dependent translocation of cohesin along DNA, a suppression relieved by Smc3 acetylation and mitotic kinases (PMID:27872142). Through continuous release-and-reload turnover, WAPL generates a pool of free cohesin required for its redistribution to cell-type-specific binding sites, so that WAPL loss paradoxically depletes cohesin from promoter-enhancer regions and disrupts cell-type-specific gene expression over the long term, even though acute WAPL loss does not perturb most enhancer-promoter loops (PMID:33318687, PMID:36471071). WAPL antagonism of cohesin is conserved and selective for kleisin identity: it acts preferentially on Scc1/COH-3/4 cohesin rather than meiotic Rec8/REC-8 cohesin, controlling meiotic chromosome structure and accurate meiosis I segregation (PMID:26841696, PMID:32328639). At centromeres, Haspin phosphorylates the WAPL YSR motif to block its interaction with Pds5B, protecting centromeric cohesion from premature release in mitosis (PMID:29138236). Beyond chromosome architecture, WAPL promotes RAD51-dependent repair and restart of stressed replication forks (PMID:32084359) and acts as a rheostat of cohesin processivity that tunes clustered Protocadherin isoform diversity governing neuronal axonal wiring (PMID:37347873).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2012 High

    Established WAPL as a conserved negative regulator of cohesin chromatin association, distinguishing its role in cohesion maintenance from cohesin's transcriptional functions and linking stable cohesin to chromatin silencing.

    Evidence Wapl deletion and epistasis with eco1 acetyltransferase mutants in budding yeast, plus dominant wapl allele and Nipped-B/pds5 epistasis on Drosophila polytene chromosomes

    PMID:23034634 PMID:23219725

    Open questions at the time
    • Did not resolve the molecular structure of the gate-opening reaction
    • Mechanism by which acetylation confers Wapl-resistance not defined at this stage
  2. 2016 High

    Defined the biochemical action of Wapl-Pds5 on the cohesin core and revealed kleisin identity as the determinant of WAPL sensitivity, explaining selective regulation of distinct cohesin populations.

    Evidence Single-molecule imaging and ATPase mutant analysis in Xenopus egg extracts; C. elegans genetic loss-of-function with cohesin subunit immunostaining in oogenesis

    PMID:26841696 PMID:27872142

    Open questions at the time
    • Did not provide an atomic structure of the open gate
    • Did not connect translocation suppression to genome-wide loop architecture
  3. 2017 High

    Connected WAPL-mediated cohesin turnover to 3D genome organization and resolved how its release activity is locally restrained at centromeres during mitosis.

    Evidence Auxin-inducible degron depletion of WAPL and PDS5 with Hi-C, ChIP-seq, and microscopy; plus Haspin in vitro kinase assays, YSR mutagenesis, and centromeric cohesion assays

    PMID:29138236 PMID:29217591

    Open questions at the time
    • Long-term versus acute consequences of turnover loss not yet separated
    • How CTCF/PDS5 dependence integrates with WAPL release not fully mapped
  4. 2017 Low

    Synthesized reconstitution data into a structural model of how Pds5-Wapl docks on Scc1 to open the Smc3-Scc1 exit gate.

    Evidence Structural/biochemical model paper integrating published reconstitution and mutagenesis data

    PMID:28220956

    Open questions at the time
    • Model paper without new primary experiments in the abstract
    • Step-by-step kinetics of gate opening not directly observed here
  5. 2020 High

    Demonstrated that WAPL turnover, rather than simple cohesin presence, is required for cell-type-specific cohesin positioning and gene expression, and extended WAPL function to meiosis and replication-stress survival.

    Evidence WAPL ablation in mouse ES cells with Hi-C/4C, ChIP-seq, RNA-seq; conditional Wapl depletion in mouse oocytes with single-nucleus Hi-C; WAPL knockout with replication fork repair and RAD51 co-localization assays

    PMID:32084359 PMID:32328639 PMID:33318687

    Open questions at the time
    • Mechanism coupling cohesin turnover to pioneer-factor-defined sites not fully resolved
    • Why oocyte loop sizes do not increase unlike somatic cells unexplained
    • Replication-stress role rests on a single-lab Medium-confidence study
  6. 2022 High

    Showed that WAPL is dispensable for short-term maintenance of most enhancer-promoter loops, refining the timescale on which its turnover activity shapes gene regulation.

    Evidence Acute auxin-inducible degron depletion of WAPL in mouse ES cells with high-resolution Micro-C and nascent transcript profiling

    PMID:36471071

    Open questions at the time
    • Does not identify which loops do depend acutely on WAPL
    • Distinction between maintenance and establishment timescales not mechanistically dissected
  7. 2023 Medium

    Established WAPL as a rheostat of cohesin processivity that tunes stochastic gene choice, linking its release activity to neuronal identity and wiring.

    Evidence Cell-type-specific manipulation of WAPL activity in mouse serotonergic and olfactory sensory neurons with Pcdh isoform profiling and axonal projection analysis

    PMID:37347873

    Open questions at the time
    • Quantitative relationship between WAPL dose and cohesin processivity not defined
    • Single study without independent confirmation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How WAPL-mediated cohesin turnover is selectively targeted, timed, and integrated across distinct biological contexts (loop extrusion, replication, meiosis, neuronal gene choice) remains incompletely resolved.
  • No unified kinetic model linking gate-opening biochemistry to context-specific outcomes
  • Regulators beyond Haspin/acetylation that locally tune WAPL activity not enumerated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005694 chromosome 3 GO:0005634 nucleus 2
Pathway
R-HSA-1640170 Cell Cycle 3 R-HSA-4839726 Chromatin organization 2 R-HSA-73894 DNA Repair 1
Partners
HASPINPDS5APDS5BRAD21SMC3
Complex memberships
cohesin

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 WAPL functions as the cohesin unloading factor that controls the length of chromatin loops genome-wide; in the absence of WAPL and its PDS5 binding partners, cohesin forms extended loops (presumably by passing CTCF sites), accumulates in axial chromosomal positions (vermicelli), and condenses chromosomes. CTCF defines TAD boundaries in a manner dependent on PDS5 proteins. Auxin-inducible degron depletion of WAPL and PDS5 proteins in human cells, combined with Hi-C, ChIP-seq, and microscopy The EMBO journal High 29217591
2020 WAPL creates a pool of free cohesin through cohesin turnover (release and reload cycle), which is required for cohesin to occupy cell-type-specific binding sites. Stabilization of cohesin binding following WAPL ablation paradoxically depletes cohesin from cell-type-specific regions, causing loss of promoter-enhancer loops and gene expression. Cohesin loading at cell-type-specific sites depends on pioneer transcription factors OCT4 and SOX2 but not NANOG. WAPL ablation in mouse embryonic stem cells combined with chromosome conformation capture (Hi-C/4C), ChIP-seq, RNA-seq, and transcription factor binding analysis Nature genetics High 33318687
2022 Acute depletion of WAPL (3 h) does not substantially affect enhancer-promoter interactions or gene expression, demonstrating that WAPL is not required for short-term maintenance of most E-P loops. Acute auxin-inducible degron depletion of WAPL in mouse embryonic stem cells, assessed by high-resolution Micro-C and nascent transcript profiling Nature genetics High 36471071
2016 Wapl-Pds5 complex suppresses the intrinsic ATPase-dependent translocation ability of the cohesin core complex along DNA; cohesin acetylation (of Smc3) and mitotic kinases alleviate this suppression, allowing cohesin translocation on unreplicated DNA in Xenopus egg extracts. Single-molecule imaging of cohesin dynamics on DNA, ATPase mutant analysis, Xenopus laevis egg extract reconstitution, and Smc3 acetylation assays The EMBO journal High 27872142
2012 Budding yeast Wapl negatively regulates cohesion maintenance in G2 by destabilizing unacetylated chromosome-bound cohesin; cohesin acetylation renders cohesin Wapl-resistant from S phase onward. Wapl is not required for cohesin's role in transcriptional regulation but loss of Wapl increases chromosome condensation in both interphase and mitosis. Wapl deletion and epistasis analysis with eco1/acetyltransferase mutants in Saccharomyces cerevisiae; sister chromatid cohesion assays and chromosome condensation measurements Current biology : CB High 23219725
2016 In C. elegans oogenesis, WAPL-1 selectively antagonizes cohesin complexes containing COH-3/4 kleisins but not REC-8-containing cohesin, demonstrating that kleisin identity determines sensitivity to WAPL-1. By restricting COH-3/4 cohesin on chromosomes, WAPL-1 controls meiotic chromosome structure throughout prophase; in the absence of REC-8, WAPL-1 inhibits COH-3/4-mediated cohesion. C. elegans genetic loss-of-function experiments, immunostaining of chromosome-associated cohesin complexes, meiotic chromosome structure analysis eLife High 26841696
2017 The kinase domain of Haspin binds and phosphorylates the YSR motif of Wapl, directly inhibiting the YSR motif-dependent interaction of Wapl with Pds5B, thereby protecting centromeric cohesion from Wapl-mediated release in mitosis. Phospho-mimetic mutation in Wapl-YSR prevents Wapl from binding Pds5B and releasing cohesin. Co-immunoprecipitation, in vitro kinase assays with Wapl YSR mutants, Haspin inhibitor treatment, forced centromere targeting of Haspin kinase domain, and centromeric cohesion assays in cells EMBO reports High 29138236
2020 WAPL promotes RAD51-dependent repair and restart of broken DNA replication forks under replication stress conditions; active cohesin removal by WAPL is required for cell growth under replication stress. WAPL depletion causes oncogene-induced loss of sister chromatid cohesion from newly synthesized sister chromatids. WAPL depletion/knockout in untransformed and cancer cell lines, oncogene induction, replication fork repair assays, RAD51 co-localization, and metaphase spread cohesion analysis Developmental cell Medium 32084359
2012 In Drosophila, Wapl protein antagonizes cohesin binding to chromosomes. A truncated dominant Wapl-AG mutant increases stability of cohesin binding to polytene chromosomes and causes Polycomb-group-like phenotypes (extra sex combs). Mutations in Nipped-B (cohesin loader) suppress, and pds5 mutations enhance, wapl mutant phenotypes, placing Wapl in the cohesin loading/unloading pathway and implicating stable cohesin as interfering with Polycomb-group silencing. Drosophila genetic screen, dominant wapl allele characterization, genetic epistasis with Nipped-B and pds5, polytene chromosome immunostaining for cohesin stability Development (Cambridge, England) Medium 23034634
2017 Pds5 and Wapl form a rigid scaffold that docks on Scc1 to open the Smc3-Scc1 DNA exit gate of cohesin; Wapl disrupts the Smc3-Scc1 interface with assistance from ATP hydrolysis, and Pds5 prolongs the open state by binding the dissociated N-terminal domain of Scc1, releasing DNA. Structural and biochemical model integrating published reconstitution and mutagenesis data on cohesin ring opening (review/model paper synthesizing experimental evidence) BioEssays : news and reviews in molecular, cellular and developmental biology Low 28220956
2020 In mouse oocytes, Wapl predominantly releases Scc1-cohesin (not Rec8-cohesin) from chromosomes. Wapl is required for accurate meiosis I chromosome segregation and production of euploid eggs. Increasing Scc1 residence time on chromosomes by Wapl depletion leads to vermicelli formation and intra-loop structures but does not increase loop size (unlike in somatic cells). Scc1 is essential for chromosome organization in oocytes. Conditional Wapl depletion in mouse oocytes, single-nucleus Hi-C, immunostaining for cohesin subunits, chromosome segregation analysis The Journal of cell biology High 32328639
2023 WAPL functions as a rheostat of cohesin processivity that determines the diversity of clustered Protocadherin (Pcdh) isoform expression in neurons. While cohesin erases genomic-distance biases in Pcdh gene choice, WAPL modulates cohesin processivity to control cell-type-specific Pcdh expression patterns and consequently axonal wiring specificity. Cell-type-specific manipulation of WAPL activity in mouse serotonergic and olfactory sensory neurons, Pcdh isoform expression profiling, axonal projection analysis Science (New York, N.Y.) Medium 37347873

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Myeloperoxidase: friend and foe. Journal of leukocyte biology 1661 15689384
2019 Neuroinflammation: friend and foe for ischemic stroke. Journal of neuroinflammation 1147 31291966
2017 Topologically associating domains and chromatin loops depend on cohesin and are regulated by CTCF, WAPL, and PDS5 proteins. The EMBO journal 622 29217591
2012 Tumor-associated neutrophils: friend or foe? Carcinogenesis 550 22425643
2020 Exercise-induced oxidative stress: Friend or foe? Journal of sport and health science 451 32380253
2009 Nrf2: friend or foe for chemoprevention? Carcinogenesis 362 19793802
2018 Interleukin-1 Beta-A Friend or Foe in Malignancies? International journal of molecular sciences 358 30042333
2006 Cardiac fibroblasts: friend or foe? American journal of physiology. Heart and circulatory physiology 339 16617141
2008 The osteoclast: friend or foe? Annual review of pathology 324 18039135
2022 Enhancer-promoter interactions and transcription are largely maintained upon acute loss of CTCF, cohesin, WAPL or YY1. Nature genetics 314 36471071
2018 Nutrients and Oxidative Stress: Friend or Foe? Oxidative medicine and cellular longevity 247 29643982
2016 ICOS Co-Stimulation: Friend or Foe? Frontiers in immunology 237 27559335
2018 Ubiquitination: Friend and foe in cancer. The international journal of biochemistry & cell biology 226 29864543
2014 Protein phosphorylation in neurodegeneration: friend or foe? Frontiers in molecular neuroscience 200 24860424
2013 Autophagy: cancer's friend or foe? Advances in cancer research 183 23768510
2000 Dinucleoside polyphosphates-friend or foe? Pharmacology & therapeutics 163 11007992
2017 AGEs, RAGEs and s-RAGE; friend or foe for cancer. Seminars in cancer biology 157 28712719
2016 Gamma-glutamyltransferase-friend or foe within? Liver international : official journal of the International Association for the Study of the Liver 138 27512925
2020 G-Quadruplexes at Telomeres: Friend or Foe? Molecules (Basel, Switzerland) 137 32823549
2020 WAPL maintains a cohesin loading cycle to preserve cell-type-specific distal gene regulation. Nature genetics 137 33318687
2017 STAT1 in cancer: friend or foe? Discovery medicine 127 28950072
2019 Rho GTPases in cancer: friend or foe? Oncogene 126 31427738
2014 Protein mistranslation: friend or foe? Trends in biochemical sciences 125 25023410
2018 Crosstalk between phosphorylation and O-GlcNAcylation: friend or foe. The FEBS journal 123 29717537
2018 NFKB1 and Cancer: Friend or Foe? Cells 103 30205516
2016 Cohesin acetylation and Wapl-Pds5 oppositely regulate translocation of cohesin along DNA. The EMBO journal 101 27872142
2023 Inflammation in pathogenesis of chronic pain: Foe and friend. Molecular pain 99 37220667
2012 Budding yeast Wapl controls sister chromatid cohesion maintenance and chromosome condensation. Current biology : CB 98 23219725
2020 Zinc in the Brain: Friend or Foe? International journal of molecular sciences 92 33255662
2006 Adenovirus: from foe to friend. Reviews in medical virology 79 16710837
2019 Role of autophagy in atherosclerosis: foe or friend? Journal of inflammation (London, England) 77 31073280
2014 Estrogen receptor beta in prostate cancer: friend or foe? Endocrine-related cancer 76 24402043
2020 Platelets in Neurodegenerative Conditions-Friend or Foe? Frontiers in immunology 74 32431701
2018 PGC1α: Friend or Foe in Cancer? Genes 74 29361779
2019 Friend or foe-IDH1 mutations in glioma 10 years on. Carcinogenesis 72 31504231
2008 Amyloids: friend or foe? Journal of Alzheimer's disease : JAD 72 18487849
2019 SOX11: friend or foe in tumor prevention and carcinogenesis? Therapeutic advances in medical oncology 70 31210798
2016 Friend or foe? The tumour microenvironment dilemma in colorectal cancer. Biochimica et biophysica acta. Reviews on cancer 70 27864070
2022 The Role of SLC7A11 in Cancer: Friend or Foe? Cancers 68 35804831
2021 Pyroptosis in Cancer: Friend or Foe? Cancers 68 34298833
2017 Protein kinase D signaling in cancer: A friend or foe? Biochimica et biophysica acta. Reviews on cancer 68 28577984
2021 NF-κB in Cancer Immunity: Friend or Foe? Cells 64 33572260
2016 Cancer and necroptosis: friend or foe? Cellular and molecular life sciences : CMLS 64 27048810
2019 Friend or foe, the role of EGR-1 in cancer. Medical oncology (Northwood, London, England) 63 31748910
2024 The Multifaceted Roles of NRF2 in Cancer: Friend or Foe? Antioxidants (Basel, Switzerland) 62 38247494
2015 Lithium in the Kidney: Friend and Foe? Journal of the American Society of Nephrology : JASN 61 26577775
2012 GLP1 and cancer: friend or foe? Endocrine-related cancer 58 22691625
2010 Cannabinoids and bone: friend or foe? Calcified tissue international 58 20532878
2017 STING signaling in tumorigenesis and cancer therapy: A friend or foe? Cancer letters 55 28602976
2016 Cohesin-interacting protein WAPL-1 regulates meiotic chromosome structure and cohesion by antagonizing specific cohesin complexes. eLife 55 26841696
2015 Phosphoinositide 3-kinase: friend and foe in cardiovascular disease. Frontiers in pharmacology 55 26321955
2009 Magnesium and tumors: ally or foe? Cancer treatment reviews 55 19203841
2023 WAPL functions as a rheostat of Protocadherin isoform diversity that controls neural wiring. Science (New York, N.Y.) 54 37347873
2018 MDR1 in immunity: friend or foe? Oncoimmunology 54 30524890
2016 MTH1 as a nucleotide pool sanitizing enzyme: Friend or foe? Free radical biology & medicine 54 27833032
2018 B7-H3 in tumors: friend or foe for tumor immunity? Cancer chemotherapy and pharmacology 50 29299639
2013 Megalin in acute kidney injury: foe and friend. American journal of physiology. Renal physiology 50 24197071
2022 Microglia: Friend and foe in tauopathy. Progress in neurobiology 49 35714860
2024 Friend or foe: The role of stress granule in neurodegenerative disease. Neuron 47 38744273
2021 ER Stress and Unfolded Protein Response in Leukemia: Friend, Foe, or Both? Biomolecules 47 33573353
2017 A kinase-dependent role for Haspin in antagonizing Wapl and protecting mitotic centromere cohesion. EMBO reports 47 29138236
2018 Friend or foe: Signaling mechanisms during double fertilization in flowering seed plants. Current topics in developmental biology 46 30612627
2022 TLR9: A friend or a foe. Life sciences 45 35963302
2018 The mitochondria in lung fibrosis: friend or foe? Translational research : the journal of laboratory and clinical medicine 44 30036495
2021 Post-stroke Neurogenesis: Friend or Foe? Frontiers in cell and developmental biology 43 33834025
2020 WAPL-Dependent Repair of Damaged DNA Replication Forks Underlies Oncogene-Induced Loss of Sister Chromatid Cohesion. Developmental cell 43 32084359
2014 Stat3: friend or foe in colitis and colitis-associated cancer? Inflammatory bowel diseases 43 25185686
2023 ARID1A in cancer: Friend or foe? Frontiers in oncology 42 36890819
2020 Malignancy and IFITM3: Friend or Foe? Frontiers in oncology 42 33364194
2014 Mitochondrial stress: balancing friend and foe. Experimental gerontology 42 24603155
2014 TLR4 in Toxoplasmosis; friends or foe? Microbial pathogenesis 42 24685700
2020 Tim-4 in Health and Disease: Friend or Foe? Frontiers in immunology 41 32300343
2020 p62: Friend or Foe? Evidences for OncoJanus and NeuroJanus Roles. International journal of molecular sciences 41 32708719
2022 Browning Epicardial Adipose Tissue: Friend or Foe? Cells 39 35326442
2020 The Aryl Hydrocarbon Receptor in Asthma: Friend or Foe? International journal of molecular sciences 39 33233810
2018 KISS1/KISS1R in Cancer: Friend or Foe? Frontiers in endocrinology 39 30123188
2023 TP53 Mutation in Acute Myeloid Leukemia: An Old Foe Revisited. Cancers 38 37835510
2021 Natural Killer Cells: Friend or Foe in Metabolic Diseases? Frontiers in immunology 38 33717101
2021 Neuronal Mitophagy: Friend or Foe? Frontiers in cell and developmental biology 37 33537304
2021 TNFα and Immune Checkpoint Inhibition: Friend or Foe for Lung Cancer? International journal of molecular sciences 37 34445397
2012 Wapl antagonizes cohesin binding and promotes Polycomb-group silencing in Drosophila. Development (Cambridge, England) 36 23034634
2023 The intratumoral microbiota: friend or foe? Trends in cancer 35 37061408
2021 PERK signaling pathway in bone metabolism: Friend or foe? Cell proliferation 35 33615575
2020 Friend or foe? Lactobacillus in the context of autoimmune disease. Advances in immunology 35 32327152
2019 LRRK2 in Infection: Friend or Foe? ACS infectious diseases 35 30915830
2022 The chaperone Clusterin in neurodegeneration-friend or foe? BioEssays : news and reviews in molecular, cellular and developmental biology 34 35521968
2007 COX-2: friend or foe? Current pharmaceutical design 34 17584101
2019 EGFR Signaling: Friend or Foe for Cartilage? JBMR plus 33 30828691
2017 The Top1 paradox: Friend and foe of the eukaryotic genome. DNA repair 33 28641942
2020 The proteasome: friend and foe of mitochondrial biogenesis. FEBS letters 31 33249599
2016 Potassium: friend or foe? Pediatric nephrology (Berlin, Germany) 31 27194424
2024 Friend or foe: Lactate in neurodegenerative diseases. Ageing research reviews 30 39127445
2017 Releasing the cohesin ring: A rigid scaffold model for opening the DNA exit gate by Pds5 and Wapl. BioEssays : news and reviews in molecular, cellular and developmental biology 30 28220956
2022 APOBEC3: Friend or Foe in Human Papillomavirus Infection and Oncogenesis? Annual review of virology 29 35671565
2021 Inflammasomes in dendritic cells: Friend or foe? Immunology letters 29 33848562
2022 Nutritional Sensor REDD1 in Cancer and Inflammation: Friend or Foe? International journal of molecular sciences 28 36077083
2020 Wapl releases Scc1-cohesin and regulates chromosome structure and segregation in mouse oocytes. The Journal of cell biology 28 32328639
2018 Molecular Regulation of Carcinogenesis: Friend and Foe. Toxicological sciences : an official journal of the Society of Toxicology 27 30053205
2023 Extracellular vesicles and COPD: foe or friend? Journal of nanobiotechnology 26 37147634
2020 Candidate rejuvenating factor GDF11 and tissue fibrosis: friend or foe? GeroScience 26 33025411

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