Affinage

RAD21

Double-strand-break repair protein rad21 homolog · UniProt O60216

Length
631 aa
Mass
71.7 kDa
Annotated
2026-06-10
100 papers in source corpus 39 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAD21 is the kleisin subunit of the cohesin ring, where it bridges SMC1 and SMC3 together with the SA/STAG subunits to topologically entrap sister chromatids and enforce cohesion until anaphase (PMID:23874961, PMID:11069892, PMID:12573216). Its central regulatory event is proteolytic: separase cleaves RAD21 (Scc1) at anaphase onset to dissolve cohesion, and a cleavage-resistant kleisin blocks sister chromatid separation (PMID:10403247). This cleavage is licensed by phosphorylation — Polo/Cdc5 kinase phosphorylates residues adjacent to the cleavage sites to enhance separase action, while CDK and ATR phosphorylate the central domain to couple cohesin removal to mitosis and to the completion of DNA repair (PMID:11371343, PMID:18239448). Cohesin's chromosomal residence is set by opposing loading and release machineries that act through RAD21: the Scc2/NIPBL loader engages the Scc1-binding site to stimulate ATPase-dependent loading, whereas Pds5 binds the same kleisin surface to define a releasing/Wapl-antagonized state, with arm cohesin removed by opening the Smc3-Scc1 gate (PMID:29932904, PMID:26923598, PMID:26923589, PMID:23361318). RAD21 contacts the SA subunits through defined N-terminal and middle α-helical motifs whose disruption abolishes cohesion without perturbing the SMC1-SMC3-RAD21 core (PMID:23874961). Loss of RAD21 causes premature sister separation, failure of tension-dependent kinetochore biorientation, and defective homologous recombination and DNA-damage repair, and is embryonic-lethal in mice (PMID:11740938, PMID:14749720, PMID:20711430). Beyond mitosis, RAD21-cohesin organizes interphase genome architecture through chromatin loop extrusion and TAD formation in a loader-interaction-dependent manner, and acts as a transcriptional regulator at CTCF-independent sites and pluripotency/PRC2 loci (PMID:37381036, PMID:32328639, PMID:21589869, PMID:27554164). RAD21 is also a caspase substrate during apoptosis: cleavage at Asp-279 generates a C-terminal fragment that translocates to the cytoplasm and amplifies the death signal (PMID:12417729, PMID:11875078). Human RAD21 mutations cause a cohesinopathy/Cornelia de Lange-type phenotype and have been linked to chronic intestinal pseudo-obstruction through loss of transcriptional repressor function (PMID:22633399, PMID:39984730, PMID:25575569).

Mechanistic history

Synthesis pass · year-by-year structured walk · 31 steps
  1. 1999 High

    Established the central mechanism dissolving sister chromatid cohesion: separase proteolysis of the kleisin, answering how anaphase is triggered.

    Evidence In vitro cleavage assay and cleavage-resistant mutant expression in S. cerevisiae

    PMID:10403247

    Open questions at the time
    • Did not define how cleavage is temporally restricted to anaphase
    • Human ortholog cleavage not yet characterized
  2. 2000 High

    Showed RAD21 is a stable cohesin subunit assembled with SMC proteins, loaded onto chromatin by a dedicated loader, and cleaved in vivo, generalizing the cohesin model to fission yeast.

    Evidence Reciprocal Co-IP, ChIP, and in vivo cleavage assay in S. pombe

    PMID:11069892

    Open questions at the time
    • Stoichiometry and ring topology not resolved
    • Loader mechanism not defined
  3. 2000 Medium

    Defined distinct subcellular pools of RAD21 and identified its nuclear-matrix/nuclear localization determinants, framing where the protein acts during the cell cycle.

    Evidence Live imaging of GFP fusions in Drosophila S2/embryos; fractionation and in vitro matrix-binding for the human ortholog

    PMID:10623634 PMID:11102811

    Open questions at the time
    • Functional role of centrosome/cytoplasmic pools not mechanistically defined
    • Matrix-binding region mapped only by in vitro assay
  4. 2001 High

    Linked phosphorylation to cleavage control: Polo kinase phosphorylation near the cleavage sites enhances separase action, explaining a securin-independent regulatory layer.

    Evidence In vitro kinase assay and phospho-site mutagenesis in S. cerevisiae

    PMID:11371343

    Open questions at the time
    • In vivo kinase responsible in vertebrates not established
    • Counteracting phosphatases not identified here
  5. 2001 High

    Demonstrated the cellular phenotypes of RAD21 loss in vertebrates, separating cohesion from condensation and revealing DNA-repair and chromosome-alignment functions.

    Evidence Conditional gene deletion in chicken DT40 cells with immunofluorescence and survival readouts

    PMID:11740938

    Open questions at the time
    • Mechanism connecting cohesin to INCENP localization unresolved
    • Repair defect mechanism not defined
  6. 2002 Medium

    Defined the spindle-checkpoint consequences of cohesion loss and placed RAD21 cleavage upstream of anaphase spindle elongation.

    Evidence Genetic epistasis with Mad2/Bub1 and non-cleavable dominant-negative Rad21 in S. pombe

    PMID:11882285

    Open questions at the time
    • Single-organism genetic inference
    • Molecular link to kinetochore-microtubule attachment not directly shown
  7. 2002 High

    Identified a separase-independent fate for RAD21: caspase cleavage at Asp-279 generating a proapoptotic cytoplasmic fragment, connecting cohesin to cell-death signaling.

    Evidence In vitro caspase cleavage, site mutagenesis, fractionation, and overexpression apoptosis assays in human cells (two independent labs)

    PMID:11875078 PMID:12417729

    Open questions at the time
    • Physiological trigger and contribution to endogenous apoptosis unclear
    • Mechanism of cytoplasmic proapoptotic action not defined
  8. 2004 High

    Showed the principal mitotic role of cohesin is to generate inter-sister tension permitting biorientation, distinguished from kinetochore assembly.

    Evidence Conditional DT40 deletion with topoisomerase II epistasis and checkpoint immunofluorescence

    PMID:14749720

    Open questions at the time
    • How tension is sensed mechanistically not resolved
  9. 2004 Medium

    Extended RAD21 cohesion function to meiosis, localizing it to synaptonemal complex elements and centromeres across meiotic stages.

    Evidence Immunofluorescence co-localization in mouse spermatocytes

    PMID:15031719

    Open questions at the time
    • Causal requirement in meiosis not tested by depletion here
    • Distinction from meiotic kleisin REC8 not addressed
  10. 2007 High

    Mapped the kinase code on RAD21's central domain, assigning Polo/CDK to mitotic cleavage and ATR to post-repair cohesin removal.

    Evidence Mass spectrometry, phospho-antibodies, and kinase-mutant/DNA-damage analysis in S. pombe

    PMID:18239448

    Open questions at the time
    • Site-by-site functional contribution not fully dissected
    • Vertebrate conservation of all sites not established
  11. 2010 Medium

    Revealed a cohesion-independent role for RAD21 at centrosomes, linking centrosome integrity to cohesion regulators.

    Evidence siRNA depletion, immunofluorescence, and regulator-dependency analysis in human cells

    PMID:20404533 PMID:20404544

    Open questions at the time
    • Molecular function of RAD21 at centrosomes undefined
    • Single-lab observation
  12. 2010 High

    Established organismal and DNA-repair requirements: Rad21 is essential for embryogenesis and dose-dependently supports homologous recombination and tissue regeneration after irradiation.

    Evidence Targeted mouse knockout with HR, SCE, and radiation-survival assays

    PMID:20711430

    Open questions at the time
    • Mechanism of haploinsufficient repair defect not resolved
  13. 2011 High

    Identified calpain-1 as a third RAD21 protease, defining a calcium-dependent pathway for cohesin removal and arm separation.

    Evidence In vitro calpain cleavage, cleavage-site mutagenesis, and fractionation in human cells

    PMID:21876002

    Open questions at the time
    • Physiological context where calpain cleavage operates unclear
    • Single-lab finding
  14. 2011 Medium

    Connected RAD21-cohesin to pluripotency gene regulation at CTCF-independent sites bound by core stemness factors.

    Evidence ChIP-seq, RNAi transcriptome, and Co-IP in embryonic stem cells

    PMID:21589869

    Open questions at the time
    • Direct vs architectural mechanism of co-regulation not separated
    • Single-lab dataset
  15. 2012 High

    Defined sumoylation of RAD21 by Mms21 as a DNA-damage-specific regulatory mark promoting sister chromatid recombination upstream of Wapl antagonism.

    Evidence In vivo sumoylation assay, non-sumoylatable mutant, laser damage, and Wapl epistasis

    PMID:22751501

    Open questions at the time
    • Mechanism by which SUMO modulates Wapl at damage sites not resolved
  16. 2012 Medium

    Linked specific RAD21 interface mutations to human cohesinopathy, distinguishing dominant-missense from loss-of-function severity.

    Evidence Cellular DNA-damage assay, zebrafish morpholino, and patient mutation mapping

    PMID:22633399

    Open questions at the time
    • Genotype-phenotype mechanism at molecular resolution incomplete
    • Morpholino specificity caveats
  17. 2013 High

    Resolved the directional ring dynamics: cohesin loads through the Smc1-Smc3 hinge and is released by opening the Smc3-Scc1 gate during the prophase pathway.

    Evidence Interface mutagenesis and biochemical fractionation in human cells

    PMID:23361318

    Open questions at the time
    • Coordination of gate opening with Wapl/Pds5 in vivo not fully reconstituted
  18. 2016 High

    Provided structural basis for Pds5 binding along the RAD21 kleisin, defining the releasing-state architecture and its requirement for cohesion.

    Evidence X-ray crystallography with interface mutagenesis, IP, ChIP-seq, and viability assays

    PMID:26923589 PMID:26923598

    Open questions at the time
    • Dynamic exchange between Pds5- and Scc2-bound states not captured by static structure
  19. 2016 High

    Mapped the SA-binding determinants on RAD21, showing two motifs mediate SA1/2 association independent of the SMC core and are required for cohesion.

    Evidence In vitro binding, mutagenesis, Co-IP, and functional rescue in human cells

    PMID:23874961

    Open questions at the time
    • Structural detail of the middle-motif interaction not solved here
  20. 2016 Medium

    Identified co-translational N-terminal acetylation of RAD21 by Naa50 as required for proper Scc1-Smc3 interaction and cohesion establishment.

    Evidence Genetic analysis, Co-IP, and acetylation assay in Drosophila

    PMID:27996020

    Open questions at the time
    • Direct biochemical demonstration of acetylation-dependent Smc3 binding limited
    • Vertebrate conservation untested here
  21. 2016 High

    Connected RAD21-cohesin to epigenetic gene repression, showing cohesin-PRC2 co-occupancy controls Hoxa loci and stem-cell self-renewal.

    Evidence RNAi, H3K27me3 ChIP, Co-IP, and colony-forming epistasis in hematopoietic progenitors

    PMID:27554164

    Open questions at the time
    • Whether cohesin recruits PRC2 or vice versa not resolved
  22. 2017 High

    Revealed a phosphorylation-dependent second Wapl anti-cohesion pathway, with PP4 dephosphorylating RAD21's central domain to enable release.

    Evidence Co-IP, phosphomimetic/alanine alleles, and genetic epistasis in S. pombe

    PMID:28438891

    Open questions at the time
    • Conservation of this PP4-Wapl mechanism in vertebrates not tested
  23. 2017 Medium

    Identified PP2A as a stabilizer of RAD21 protein by protecting it from proteasomal degradation, adding a turnover-level control.

    Evidence Co-IP and genetic epistasis with proteasome mutants in Drosophila

    PMID:31110215

    Open questions at the time
    • Whether PP2A acts via dephosphorylation or scaffolding unresolved
    • Single-organism evidence
  24. 2017 Medium

    Showed RAD21 functions in oncogenic transcription by partnering mutant p53 to activate pro-invasion target genes.

    Evidence Reciprocal Co-IP, ChIP, and siRNA invasion assay

    PMID:28831167

    Open questions at the time
    • Direct vs cohesin-architectural contribution to target activation unclear
    • Single-lab
  25. 2017 Medium

    Demonstrated that caspase cleavage of RAD21 can rewire viral genome conformation, linking cohesin proteolysis to KSHV latency control.

    Evidence Caspase cleavage assay, 3C, and ectopic cleavage-fragment expression in PEL cells

    PMID:28854249

    Open questions at the time
    • How cleavage alters conformation without complex disassembly not mechanistically defined
  26. 2018 High

    Defined the loading-competent state: Scc2 transiently replaces Pds5 at the RAD21 site to stimulate ATP hydrolysis required for loading and translocation.

    Evidence ATPase and loading assays, ChIP, and mutant analysis in S. cerevisiae

    PMID:29932904

    Open questions at the time
    • Structural transition between Scc2- and Pds5-bound states not captured
  27. 2020 High

    Established Scc1-cohesin as the substrate of Wapl-mediated release governing interphase genome organization, with Wapl controlling loop dynamics.

    Evidence Single-nucleus Hi-C and Wapl depletion in mouse oocytes

    PMID:32328639

    Open questions at the time
    • Mechanistic basis for vermicelli/intra-loop formation not fully explained
  28. 2021 High

    Showed RAD21 dosage buffers replication stress, explaining selection for RAD21 copy gain in EWS-FLI1 Ewing sarcoma.

    Evidence Trisomy selection, ectopic expression, copy deletion, and replication-stress/proliferation assays

    PMID:33766983

    Open questions at the time
    • Molecular mechanism coupling cohesin level to replication-fork protection not defined
  29. 2022 Medium

    Identified RAD21 as a transcriptional corepressor partnering YAP/TEAD4 and recruiting NuRD to suppress interferon signaling and limit antitumor immunity.

    Evidence Co-IP, ChIP, syngeneic tumor models, and T-cell flow cytometry

    PMID:36201246

    Open questions at the time
    • Direct vs architectural mechanism of interferon repression not separated
    • Single-lab
  30. 2023 High

    Established that RAD21 levels control loop extrusion via enhanced loader interaction rather than complex abundance alone, refining how cohesin shapes the genome.

    Evidence Super-resolution imaging, Hi-C, and subunit overexpression/interaction analysis

    PMID:37381036

    Open questions at the time
    • Quantitative relationship between loader engagement and loop output not fully modeled
  31. 2025 High

    Identified a speckle-targeting motif in RAD21 that tethers chromatin to nuclear speckles to potentiate gene inducibility, disrupted in Cornelia de Lange syndrome.

    Evidence STM mutagenesis, WAPL depletion, chromatin-speckle assays, and patient-cell analysis

    PMID:39984730

    Open questions at the time
    • Speckle-tethering partners of the STM not identified
    • Generality across gene classes untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RAD21's many post-translational marks (phosphorylation, sumoylation, N-acetylation) are integrated with loader/release dynamics to switch cohesin between cohesive, loop-extruding, and transcriptional states remains unresolved.
  • No unified model couples modification state to functional output
  • Cross-talk between mitotic and interphase regulation undefined
  • Direct structural transitions during loop extrusion not visualized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0005198 structural molecule activity 3 GO:0060090 molecular adaptor activity 3 GO:0003677 DNA binding 2
Localization
GO:0005694 chromosome 3 GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 2 GO:0005815 microtubule organizing center 2 GO:0005829 cytosol 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1640170 Cell Cycle 3 R-HSA-4839726 Chromatin organization 3 R-HSA-73894 DNA Repair 3 R-HSA-5357801 Programmed Cell Death 2
Partners
NIPBL/SCC2PDS5SMC1SMC3STAG1/STAG2 (SA1/SA2)TP53WAPLYAP/TEAD4
Complex memberships
cohesin complex

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Separase (Esp1) triggers sister chromatid separation at anaphase onset by directly cleaving the cohesin subunit Scc1 (RAD21 ortholog) proteolytically, causing its dissociation from chromosomes; a cleavage-resistant Scc1 mutant blocks both sister chromatid separation and Scc1 dissociation from chromosomes. In vitro cleavage assay, cleavage-resistant mutant expression, biochemical fractionation in S. cerevisiae Nature High 10403247
2001 Polo/Cdc5 kinase phosphorylates serine residues adjacent to Scc1 cleavage sites in S. cerevisiae, strongly enhancing separase-mediated cleavage and thereby regulating sister chromatid separation independently of securin. In vitro kinase assay, phospho-site mutagenesis, genetic analysis in S. cerevisiae Cell High 11371343
2000 In S. pombe, Rad21 forms a stable cohesin complex with Psm1 and Psm3 (but not Psc3) as shown by immunoprecipitation; Rad21 is phosphorylated during S phase and is cleaved at anaphase in an amount sufficient to be essential for sister chromatid separation; chromatin IP shows cohesin enrichment at centromeres; Mis4 is required for loading Rad21 onto chromatin. Immunoprecipitation, chromatin immunoprecipitation, in vivo cleavage assay in S. pombe Genes & development High 11069892
2001 Genetic deletion of Scc1 in chicken DT40 cells causes premature sister chromatid separation without disrupting chromosome condensation; Scc1-deficient cells show defective DNA damage repair, chromosome alignment failure, and abnormal INCENP (but not CENP-C or CENP-H) localization at centromeres. Conditional gene deletion in DT40 cells, immunofluorescence, survival assay Developmental cell High 11740938
2002 Human RAD21 (hRad21) is cleaved at Asp-279 by caspases-3 and -7 during apoptosis, generating a 64-kDa C-terminal product that translocates from nucleus to cytoplasm early in apoptosis; overexpression of this cleavage product induces apoptosis in multiple cell lines, functioning as a positive feedback amplifier of the cell death signal. In vitro caspase cleavage assay, site-directed mutagenesis, subcellular fractionation, overexpression in cell lines with apoptosis readouts Molecular and cellular biology High 12417729
2002 Caspases-3 and -7 preferentially cleave human RAD21 at Asp(279) in vitro, and RAD21 is proteolyzed to a ~65-kDa C-terminal product during apoptosis in cells; caspase proteolysis of RAD21 partially removes it from chromatin and generates a proapoptotic fragment, functionally distinct from its mitotic cleavage by separase. Expression cloning, in vitro caspase cleavage assay, chromatin fractionation, cell death assays The Journal of biological chemistry High 11875078
2000 In Drosophila, DRAD21 exists in four distinct subcellular pools: cytoplasmic, chromosome-associated (dissociates in prophase), centrosome-associated (metaphase-anaphase), and a centromere-proximal pool that persists on condensed chromosomes until the metaphase-anaphase transition to maintain sister chromatid cohesion. Live imaging of DRAD21-GFP fusion in S2 cells and embryos, immunofluorescence Current biology : CB High 11102811
2003 In Drosophila cells depleted of Drad21 by RNAi, the cohesin subunit SA becomes unstable (degraded), but not the converse; Drad21 depletion causes mitotic delay in prometaphase with premature sister chromatid separation, abnormal spindle morphology, and disrupted INCENP dynamics, confirming Drad21 is required for cohesin complex stability. dsRNA-mediated RNAi in Drosophila S2 cells, western blot for protein stability, live imaging Current biology : CB High 12573216
2004 In vertebrate cells conditionally deficient in Scc1, chromosomes fail to achieve tension-dependent biorientation at kinetochores with elevated BubR1 spindle checkpoint signal; topoisomerase II inhibition can bypass the cohesin requirement, indicating Scc1's principal mitotic role is establishing inter-sister tension to allow biorientation rather than kinetochore assembly per se. Conditional gene deletion in DT40 cells, epistasis with topoisomerase II inhibitor, immunofluorescence for checkpoint proteins EMBO reports High 14749720
2012 The Smc5/6 subunit Mms21 sumoylates multiple lysines of cohesin subunit Scc1; cells expressing non-sumoylatable Scc1 (15KR mutant) maintain mitotic sister chromatid cohesion but are defective in sister chromatid recombination and sensitive to ionizing radiation; depletion of Wapl rescues SCR defects, placing Scc1 sumoylation upstream of Wapl antagonism at DNA damage sites. In vivo sumoylation assay, laser-induced DNA damage, non-sumoylatable mutant expression, epistasis with Wapl depletion Genes & development High 22751501
2013 Prophase pathway-dependent removal of human cohesin from chromosome arms requires opening of the Smc3-Scc1 gate (dissociation of Smc3 from Scc1), but not the other two cohesin ring gates; conversely, loading of human cohesin onto chromatin in telophase occurs through the Smc1-Smc3 hinge. In vitro gate-opening assay, Smc3-Scc1 interface mutagenesis, biochemical fractionation in human cells The EMBO journal High 23361318
2013 SA2 interacts with Rad21 through a broad region (aa 301–750); Rad21 binds SA proteins through two SA-binding motifs: N-terminal (aa 60–81) and middle part (aa 383–392, an α-helical motif); mutation of three residues (L385, F389, T390) or deletion of 10 aa in the MP motif disrupts Rad21-SA1/2 interaction without affecting Smc1-Smc3-Rad21 interaction; mutant Rad21 fails to rescue premature sister chromatid separation. In vitro binding assay, mutagenesis, co-immunoprecipitation, functional rescue in cells PloS one High 23874961
2011 Calpain-1 (a calcium-dependent cysteine endopeptidase) cleaves Rad21 at L192 in a calcium-dependent manner; calpain-1 normally localizes to interphase nuclei and chromatin; Rad21 cleavage by calpain-1 promotes chromosome arm separation coinciding with calcium-induced cohesin loss at chromosomal loci, defining a novel pathway for sister chromatid separation. In vitro cleavage assay with calpain-1, site-directed mutagenesis, subcellular fractionation, engineered cleavage site experiments Molecular and cellular biology High 21876002
2016 Crystal structure of Pds5 from L. thermotolerans solved in the presence and absence of bound Scc1; Scc1 binds along the spine of the Pds5 HEAT repeat fold, wedged between the spine and C-terminal hook; mutations confirming this binding mode were validated by immunoprecipitation and calibrated ChIP-seq. X-ray crystallography, mutagenesis, immunoprecipitation, ChIP-seq Cell reports High 26923598
2016 Crystal structure of Pds5 in complex with Scc1 reveals that Pds5 forms an elongated HEAT repeat that binds Scc1 via a conserved surface patch; disruption of the Pds5-Scc1 interface abolishes Pds5 recruitment to cohesin and results in loss of sister chromatid cohesion and cell inviability. X-ray crystallography, interface mutagenesis, cell viability assay, cohesion assay in yeast Cell reports High 26923589
2018 Scc2 transiently replaces Pds5 at the Scc1-binding site; Scc1 mutations that compromise its interaction with Scc2 reduce cohesin's ATPase activity and loading; Scc2 stimulates ATP hydrolysis required for cohesin loading and translocation from loading sites, defining a loading-competent state distinct from the Pds5-bound releasing state. ATPase assay, cohesin loading assay, chromatin IP, mutant analysis in S. cerevisiae Molecular cell High 29932904
1995 The S. pombe Rad21 protein is a nuclear phosphoprotein; it is multiply phosphorylated primarily at serine residues in a cell-cycle-regulated manner peaking in S-G2; the radiosensitive rad21-45 mutant protein is permanently hypophosphorylated; the nuclear localization signal is in the C-terminal third of the protein. Cell fractionation, phosphorylation analysis, cell cycle synchronization, mutant characterization in S. pombe The Journal of biological chemistry Medium 7706319
2007 Mass spectrometry identified nine phosphorylation sites in the central domain of S. pombe Rad21; Polo/Plo1 and CDK phosphorylate Rad21 in mitosis (facilitating separase cleavage and dissociation), Rad3/ATR phosphorylates Rad21 in DNA-damaged post-replicative cells (required for cohesin removal by separase after repair completion), and additional S/TP-consensus kinases phosphorylate in vegetative/G0 cells. Mass spectrometry, anti-phospho antibodies, kinase mutant analysis, DNA damage experiments in S. pombe Cell cycle (Georgetown, Tex.) High 18239448
2017 PP4 phosphatase physically associates with Wpl1 and cohesin; Wpl1 triggers Rad21 de-phosphorylation in a PP4-dependent manner at residues in the central domain of Rad21; phospho-mimicking Rad21 alleles dampen Wpl1 anti-cohesion activity, revealing a second Wpl1 anti-cohesion pathway regulated by the phosphorylation status of the kleisin Rad21. Co-immunoprecipitation, phospho-mimicking and alanine mutant alleles, genetic epistasis screen in S. pombe The EMBO journal High 28438891
2016 Naa50/San N-terminally acetylates nascent Scc1 (RAD21) polypeptide co-translationally; this modification is required for correct interaction between Scc1 and Smc3 and for establishment/maintenance of sister chromatid cohesion in Drosophila. Genetic analysis, co-immunoprecipitation, N-terminal acetylation assay in Drosophila Scientific reports Medium 27996020
2004 Mouse RAD21/SCC1 associates with axial/lateral elements of the synaptonemal complex along chromosome arms and at centromeres in spermatocytes; RAD21 is lost from chromosome arms in late prophase I but persists on centromeres until anaphase II when sister chromatids separate, supporting a role for RAD21 in meiotic sister chromatid cohesion. Immunofluorescence, co-localization with synaptonemal complex components in mouse spermatocytes EMBO reports Medium 15031719
2010 Rad21 localizes to centrosomes in human cells; Rad21 depletion disrupts centrosome integrity independently of its role in chromosome cohesion, as shown by uncoupling centrosome defects from chromosomal cohesion defects. Immunofluorescence, Rad21 depletion by siRNA, centrosome integrity assay Cell cycle (Georgetown, Tex.) Medium 20404533
2010 Rad21 localization to centrosomes depends on known regulators of sister chromatid cohesion as well as regulators of centrosome function, linking the two activities mechanistically. Immunofluorescence, dependency analysis with regulator depletions in human cells Cell cycle (Georgetown, Tex.) Medium 20404544
2010 Biallelic deletion of Rad21 in mice causes early embryonic lethality; Rad21 heterozygous cells are defective in homologous recombination-mediated gene targeting and sister chromatid exchanges; Rad21+/- animals show gastrointestinal hypersensitivity and impaired bone marrow stem cell regeneration after whole-body irradiation. Targeted gene inactivation in mice, HR assay, SCE assay, radiation survival PloS one High 20711430
2012 Human RAD21 mutations that act at the RAD21 interface with STAG2 and SMC1A impair cellular DNA damage response; in zebrafish, rad21 loss disrupts transcription; dominant missense mutations cause more severe functional defects than loss-of-function mutations, correlating with worse clinical phenotype in cohesinopathy patients. Cellular DNA damage assay, zebrafish morpholino knockdown, patient mutation mapping American journal of human genetics Medium 22633399
2011 RAD21 co-localizes with pluripotency transcription factors Oct4, Nanog, Sox2, Esrrb, and Klf4 at CTCF-independent sites in ESCs as shown by ChIP-seq; RAD21 knockdown produces gene expression changes similar to Nanog depletion; Nanog physically interacts with cohesin/cohesin-interacting proteins STAG1 and WAPL. ChIP-seq, RNAi knockdown with transcriptome analysis, co-immunoprecipitation in ESCs PloS one Medium 21589869
2016 Rad21 depletion in hematopoietic stem and progenitor cells causes derepression of PRC2 target genes Hoxa7 and Hoxa9 (with decreased H3K27me3 at their promoters), enhancing self-renewal; the cohesin and PRC2 complexes physically interact and co-occupy Hoxa7 and Hoxa9 loci; knockdown of Hoxa7 or Hoxa9 suppresses enhanced self-renewal. RNAi, ChIP for H3K27me3, co-immunoprecipitation, colony-forming assays, epistasis Leukemia High 27554164
2023 RAD21 upregulation leads to excessive chromatin loop extrusion (vermicelli morphology) with RAD21 clustering into foci; mechanistically, the effect is attributed to enhanced RAD21-loader (Scc2/NIPBL) interaction that facilitates cohesin loading rather than merely increasing cohesin complex abundance; Hi-C confirmed global chromatin structural changes. Super-resolution imaging, Hi-C, overexpression of individual cohesin subunits, interaction analysis Genome biology High 37381036
2021 In Ewing sarcoma, EWS-FLI1 causes replication stress; trisomy 8 mitigates this through gain of a RAD21 copy; low-level ectopic RAD21 expression is sufficient to dampen replication stress and improve proliferation in EWS-FLI1-expressing cells; deleting one RAD21 copy in trisomy 8 cells largely neutralizes the fitness benefit. Evolutionary approach (trisomy selection), ectopic RAD21 expression, RAD21 copy deletion, soft agar assay, replication stress markers Genes & development High 33766983
2022 RAD21 directly interacts with YAP/TEAD4 transcriptional corepressors and recruits the NuRD complex to suppress interferon signaling; RAD21 ablation in murine syngeneic tumor models potentiates anti-PD-1 efficacy with increased intratumoral CD8+ T cell effector activity. Co-immunoprecipitation, ChIP, murine syngeneic tumor model, flow cytometry for T cell subsets The Journal of clinical investigation Medium 36201246
2017 ER stress induces rapid caspase-dependent cleavage of RAD21 in KSHV-positive PEL cells; the cleaved RAD21 does not dissociate from viral genomes or disassemble the cohesin complex, but cleavage disrupts KSHV latency genome conformation (shown by 3C assay) and activates lytic gene transcription; ectopic C-terminal RAD21 cleavage product is sufficient to partially induce KSHV lytic genes. Caspase cleavage assay, chromosome conformation capture (3C), ectopic expression of cleavage fragment PLoS pathogens Medium 28854249
2017 In Drosophila, PP2A catalytic subunit (Mts) interacts with Rad21/Verthandi (Vtd); loss of Mts or its regulatory subunit Tws reduces Vtd protein level; reduced proteasome function suppresses mitotic defects from combined mts/vtd mutations, indicating PP2A stabilizes Rad21 by protecting it from proteasomal degradation. Co-immunoprecipitation, genetic epistasis with proteasome mutants, western blot for protein levels in Drosophila Scientific reports Medium 31110215
2020 Wapl predominantly releases Scc1-cohesin (not Rec8-cohesin) from mouse oocyte chromosomes; Scc1 is essential for chromosome organization in oocytes as shown by single-nucleus Hi-C; Wapl depletion increases Scc1 residence time producing vermicelli and intra-loop structures without increasing loop size. Single-nucleus Hi-C, Wapl depletion in mouse oocytes, immunofluorescence The Journal of cell biology High 32328639
2025 A speckle-targeting motif (STM) within RAD21 is required for chromatin-nuclear speckle association; depletion of WAPL (which stabilizes cohesin on chromatin) reinforces DNA-speckle contacts and enhances inducibility of speckle-associated genes; patient-derived cells with Cornelia de Lange syndrome show disrupted chromatin-speckle association. STM mutagenesis, WAPL depletion, chromatin-speckle association assay, patient cell analysis Nature structural & molecular biology High 39984730
2000 NXP-1 (human RAD21 ortholog) localizes to the nuclear matrix in HeLa cells; the N-terminal region (aa 16–128) has an important role in nuclear matrix distribution, as shown by in vitro binding assays with nuclear matrix preparations. Western blot fractionation, immunofluorescence, in vitro nuclear matrix binding assay Biochemical and biophysical research communications Medium 10623634
2002 In fission yeast, loss of chromatid cohesion in rad21-K1 mutants activates Mad2- and Bub1-dependent spindle checkpoint due to diminished microtubule-kinetochore interaction; dominant-negative non-cleavable Rad21 blocks sister chromatid separation and full spindle elongation without activating checkpoint, placing Rad21 cleavage upstream of anaphase spindle elongation. Genetic epistasis with checkpoint mutants, spindle checkpoint activation assay, dominant-negative mutant analysis in S. pombe Current biology : CB Medium 11882285
2014 Rad21 (encoded by verthandi/vtd) binds directly to the lateral SC component C(2)M in Drosophila oocytes; premature Rad21 elimination causes loss of cohesin from meiotic chromatin AND precocious synaptonemal complex disassembly; however, chromosome segregation during female meiosis does not depend on Rad21-containing cohesin (negative finding for meiotic cohesion role). Engineered Rad21 variant with inducible cleavage, co-immunoprecipitation with C(2)M, chromosome segregation assay in Drosophila oogenesis PLoS genetics Medium 25101996
2015 A homozygous RAD21 mutation (p.622 Ala>Thr) found in CIPO patients abolishes RAD21 binding to the APOB promoter and fails to repress APOB expression; wild-type RAD21 represses APOB transcription in HEK293 cells; in zebrafish, rad21a suppression reduces runx1 expression, delays intestinal transit, and reduces enteric neurons, which is rescued by human RAD21 mRNA but not the mutant allele. ChIP (promoter binding), overexpression in HEK293 cells, zebrafish morpholino with rescue experiment Gastroenterology High 25575569
2017 Mutant p53-R248 physically interacts with RAD21; this complex binds to RAD21-binding elements in the S1PR1 and THBS1 gene promoters to upregulate their expression; Rad21 knockdown attenuates mutant p53-induced cell invasion and expression of S1PR1 and THBS1. Co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown with invasion assay Scientific reports Medium 28831167

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Sister-chromatid separation at anaphase onset is promoted by cleavage of the cohesin subunit Scc1. Nature 796 10403247
2001 Phosphorylation of the cohesin subunit Scc1 by Polo/Cdc5 kinase regulates sister chromatid separation in yeast. Cell 313 11371343
2000 Characterization of fission yeast cohesin: essential anaphase proteolysis of Rad21 phosphorylated in the S phase. Genes & development 253 11069892
2001 Scc1/Rad21/Mcd1 is required for sister chromatid cohesion and kinetochore function in vertebrate cells. Developmental cell 239 11740938
2012 RAD21 mutations cause a human cohesinopathy. American journal of human genetics 228 22633399
1992 Cloning and characterization of rad21 an essential gene of Schizosaccharomyces pombe involved in DNA double-strand-break repair. Nucleic acids research 221 1480481
2002 Ptprj is a candidate for the mouse colon-cancer susceptibility locus Scc1 and is frequently deleted in human cancers. Nature genetics 200 12089527
2018 Scc2 Is a Potent Activator of Cohesin's ATPase that Promotes Loading by Binding Scc1 without Pds5. Molecular cell 136 29932904
2004 Involvement of the cohesin Rad21 and SCP3 in monopolar attachment of sister kinetochores during mouse meiosis I. Journal of cell science 126 14970259
2011 RAD21 cooperates with pluripotency transcription factors in the maintenance of embryonic stem cell identity. PloS one 108 21589869
2000 The Drosophila RAD21 cohesin persists at the centromere region in mitosis. Current biology : CB 105 11102811
2010 Rad21-cohesin haploinsufficiency impedes DNA repair and enhances gastrointestinal radiosensitivity in mice. PloS one 94 20711430
2013 Prophase pathway-dependent removal of cohesin from human chromosomes requires opening of the Smc3-Scc1 gate. The EMBO journal 92 23361318
2003 Depletion of Drad21/Scc1 in Drosophila cells leads to instability of the cohesin complex and disruption of mitotic progression. Current biology : CB 88 12573216
1995 The rad21 gene product of Schizosaccharomyces pombe is a nuclear, cell cycle-regulated phosphoprotein. The Journal of biological chemistry 88 7706319
2020 Cohesin subunit RAD21: From biology to disease. Gene 85 32687945
2012 Scc1 sumoylation by Mms21 promotes sister chromatid recombination through counteracting Wapl. Genes & development 74 22751501
2005 The C. elegans homolog of the mammalian tumor suppressor Dep-1/Scc1 inhibits EGFR signaling to regulate binary cell fate decisions. Genes & development 73 15901674
1996 Sequence conservation of the rad21 Schizosaccharomyces pombe DNA double-strand break repair gene in human and mouse. Genomics 73 8812457
2002 STAG2 and Rad21 mammalian mitotic cohesins are implicated in meiosis. EMBO reports 72 12034751
1998 Isolation of a Schizosaccharomyces pombe rad21ts mutant that is aberrant in chromosome segregation, microtubule function, DNA repair and sensitive to hydroxyurea: possible involvement of Rad21 in ubiquitin-mediated proteolysis. Genetics 71 9475720
2015 Mutations in RAD21 disrupt regulation of APOB in patients with chronic intestinal pseudo-obstruction. Gastroenterology 67 25575569
2004 A new role for the mitotic RAD21/SCC1 cohesin in meiotic chromosome cohesion and segregation in the mouse. EMBO reports 65 15031719
2002 Requirement of chromatid cohesion proteins rad21/scc1 and mis4/scc2 for normal spindle-kinetochore interaction in fission yeast. Current biology : CB 65 11882285
2004 Analysis of Scc1-deficient cells defines a key metaphase role of vertebrate cohesin in linking sister kinetochores. EMBO reports 64 14749720
2002 Linking sister chromatid cohesion and apoptosis: role of Rad21. Molecular and cellular biology 62 12417729
2014 CTCF and Rad21 act as host cell restriction factors for Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication by modulating viral gene transcription. PLoS pathogens 60 24415941
2004 RAD21 and KIAA0196 at 8q24 are amplified and overexpressed in prostate cancer. Genes, chromosomes & cancer 60 14603436
2016 The cohesin subunit Rad21 is a negative regulator of hematopoietic self-renewal through epigenetic repression of Hoxa7 and Hoxa9. Leukemia 58 27554164
2002 Caspase proteolysis of the cohesin component RAD21 promotes apoptosis. The Journal of biological chemistry 56 11875078
2001 Novel DNA sequence variants in the hHR21 DNA repair gene in radiosensitive cancer patients. International journal of radiation oncology, biology, physics 55 11483345
1992 Scc-1, a novel colon cancer susceptibility gene in the mouse: linkage to CD44 (Ly-24, Pgp-1) on chromosome 2. Oncogene 53 1347918
2018 Long Noncoding RNA Meg3 Regulates Mafa Expression in Mouse Beta Cells by Inactivating Rad21, Smc3 or Sin3α. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 52 29529600
2008 The Drosophila cohesin subunit Rad21 is a trithorax group (trxG) protein. Proceedings of the National Academy of Sciences of the United States of America 52 18713858
2021 RAD21 is a driver of chromosome 8 gain in Ewing sarcoma to mitigate replication stress. Genes & development 49 33766983
2013 A siRNA screen identifies RAD21, EIF3H, CHRAC1 and TANC2 as driver genes within the 8q23, 8q24.3 and 17q23 amplicons in breast cancer with effects on cell growth, survival and transformation. Carcinogenesis 47 24148822
2003 Distinct developmental function of two Caenorhabditis elegans homologs of the cohesin subunit Scc1/Rad21. Molecular biology of the cell 44 12808038
2017 BET-Inhibitors Disrupt Rad21-Dependent Conformational Control of KSHV Latency. PLoS pathogens 42 28107481
2022 RAD21 amplification epigenetically suppresses interferon signaling to promote immune evasion in ovarian cancer. The Journal of clinical investigation 41 36201246
2020 MiR-320b/RAD21 axis affects hepatocellular carcinoma radiosensitivity to ionizing radiation treatment through DNA damage repair signaling. Cancer science 41 33251678
2016 Crystal Structure of the Cohesin Gatekeeper Pds5 and in Complex with Kleisin Scc1. Cell reports 41 26923598
2013 Characterization of the interaction between the cohesin subunits Rad21 and SA1/2. PloS one 40 23874961
2006 Correlation of invasion and metastasis of cancer cells, and expression of the RAD21 gene in oral squamous cell carcinoma. Virchows Archiv : an international journal of pathology 39 16416296
2014 Cohesin Rad21 mediates loss of heterozygosity and is upregulated via Wnt promoting transcriptional dysregulation in gastrointestinal tumors. Cell reports 38 25464844
2016 Structure of the Pds5-Scc1 Complex and Implications for Cohesin Function. Cell reports 37 26923589
2008 Functional characterization of cohesin subunit SCC1 in Trypanosoma brucei and dissection of mutant phenotypes in two life cycle stages. Molecular microbiology 33 18554326
2020 Delineation of phenotypes and genotypes related to cohesin structural protein RAD21. Human genetics 31 32193685
2014 The cohesin subunit Rad21 is required for synaptonemal complex maintenance, but not sister chromatid cohesion, during Drosophila female meiosis. PLoS genetics 31 25101996
2023 RAD21 is the core subunit of the cohesin complex involved in directing genome organization. Genome biology 30 37381036
2011 Scc1 (CP0432) and Scc4 (CP0033) function as a type III secretion chaperone for CopN of Chlamydia pneumoniae. Journal of bacteriology 30 21571996
2017 Mutant p53 stimulates cell invasion through an interaction with Rad21 in human ovarian cancer cells. Scientific reports 29 28831167
2013 Two novel RAD21 mutations in patients with mild Cornelia de Lange syndrome-like presentation and report of the first familial case. Gene 29 24378232
2020 Wapl releases Scc1-cohesin and regulates chromosome structure and segregation in mouse oocytes. The Journal of cell biology 28 32328639
2010 Rad21 is required for centrosome integrity in human cells independently of its role in chromosome cohesion. Cell cycle (Georgetown, Tex.) 27 20404533
2021 ARID1A deficiency weakens BRG1-RAD21 interaction that jeopardizes chromatin compactness and drives liver cancer cell metastasis. Cell death & disease 25 34689165
2012 Deregulation of RAD21 and RUNX1 expression in endometrial cancer. Oncology letters 25 23205091
2002 Analyses of mRNA expression patterns of cohesin subunits Rad21 and Rec8 in mice: germ cell-specific expression of rec8 mRNA in both male and female mice. Zoological science 25 12130806
2017 Deregulation of KSHV latency conformation by ER-stress and caspase-dependent RAD21-cleavage. PLoS pathogens 24 28854249
2011 Calpain-1 cleaves Rad21 to promote sister chromatid separation. Molecular and cellular biology 24 21876002
2004 Molecular characterization of OsRAD21-1, a rice homologue of yeast RAD21 essential for mitotic chromosome cohesion. Journal of experimental botany 23 15073216
2021 LncRNA MIAT activates vascular endothelial growth factor A through RAD21 to promote nerve injury repair in acute spinal cord injury. Molecular and cellular endocrinology 21 33741460
2019 RAD21 inhibited transcription of tumor suppressor MIR4697HG and led to glioma tumorigenesis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 21 31884342
2000 Drad21, a Drosophila rad21 homologue expressed in S-phase cells. Gene 21 10854781
1999 The budding yeast cohesin gene SCC1/MCD1/RHC21 genetically interacts with PKA, CDK and APC. Current genetics 21 10654086
1998 The RHC21 gene of budding yeast, a homologue of the fission yeast rad21+ gene, is essential for chromosome segregation. Molecular & general genetics : MGG 21 9491073
2007 Cut1/separase-dependent roles of multiple phosphorylation of fission yeast cohesion subunit Rad21 in post-replicative damage repair and mitosis. Cell cycle (Georgetown, Tex.) 20 18239448
2018 The effect of aberrant expression and genetic polymorphisms of Rad21 on cervical cancer biology. Cancer medicine 18 29797792
2016 A novel RAD21 variant associated with intrafamilial phenotypic variation in Cornelia de Lange syndrome - review of the literature. Clinical genetics 16 27882533
2022 PPARγ/RAD21 alleviates peripheral secondary brain injury in rat cerebral hemorrhage model through promoting M2 polarization of microglial cells. International immunopharmacology 14 36538854
2021 Cohesin subunit Rad21 binds to the HSV-1 genome near CTCF insulator sites during latency in vivo. Journal of virology 14 33692212
2021 miR-122 Inhibits the Cervical Cancer Development by Targeting the Oncogene RAD21. Biochemical genetics 14 34191246
2020 SNAI1-Driven Sequential EMT Changes Attributed by Selective Chromatin Enrichment of RAD21 and GRHL2. Cancers 14 32370157
2020 Case Report: BAP1 Mutation and RAD21 Amplification as Predictive Biomarkers to PARP Inhibitor in Metastatic Intrahepatic Cholangiocarcinoma. Frontiers in oncology 14 33330039
2017 A second Wpl1 anti-cohesion pathway requires dephosphorylation of fission yeast kleisin Rad21 by PP4. The EMBO journal 14 28438891
2017 Genome sequence of the model plant pathogen Pectobacterium carotovorum SCC1. Standards in genomic sciences 14 29276572
2016 Naa50/San-dependent N-terminal acetylation of Scc1 is potentially important for sister chromatid cohesion. Scientific reports 14 27996020
2025 CTCF/RAD21 organize the ground state of chromatin-nuclear speckle association. Nature structural & molecular biology 13 39984730
2018 A novel RAD21 p.(Gln592del) variant expands the clinical description of Cornelia de Lange syndrome type 4 - Review of the literature. European journal of medical genetics 13 30125677
2015 Suppression of RAD21 Induces Senescence of MDA-MB-231 Human Breast Cancer Cells Through RB1 Pathway Activation Via c-Myc Downregulation. Journal of cellular biochemistry 12 26529363
2011 Knockdown of Mad2 induces osteosarcoma cell apoptosis-involved Rad21 cleavage. Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association 11 21901524
2006 The effect of single agent oral fusaric acid (FA) on the growth of subcutaneously xenografted SCC-1 cells in a nude mouse model. Investigational new drugs 11 16505952
2019 DNA topoisomerase IIα and RAD21 cohesin complex component are predicted as potential therapeutic targets in bladder cancer. Oncology letters 10 31289523
2007 Separase, securin and Rad21 in neural cell growth. Journal of cellular physiology 10 17450531
2000 NXP-1, a human protein related to Rad21/Scc1/Mcd1, is a component of the nuclear matrix. Biochemical and biophysical research communications 10 10623634
2022 GPBAR1 preserves neurite and synapse of dopaminergic neurons via RAD21-OPCML signaling: Role in preventing Parkinson's disease in mouse model and human patients. Pharmacological research 9 36152741
2019 Dysregulation of the cohesin subunit RAD21 by Hepatitis C virus mediates host-virus interactions. Nucleic acids research 9 30698808
2019 A novel RAD21 mutation in a boy with mild Cornelia de Lange presentation: Further delineation of the phenotype. European journal of medical genetics 9 30716475
2010 Determinants of Rad21 localization at the centrosome in human cells. Cell cycle (Georgetown, Tex.) 9 20404544
2024 RAD21 promotes oncogenesis and lethal progression of prostate cancer. Proceedings of the National Academy of Sciences of the United States of America 8 39190349
2022 LINC00858 promotes colon cancer progression through activation of STAT3/5 signaling by recruiting transcription factor RAD21 to upregulate PCNP. Cell death discovery 8 35468892
2023 Cohesin Subunit RAD21 Regulates the Differentiation and Self-Renewal of Hematopoietic Stem and Progenitor Cells. Stem cells (Dayton, Ohio) 7 37534584
2018 Cohesin RAD21 Gene Promoter Methylation in Patients with Chronic Lymphocytic Leukemia. Cytogenetic and genome research 7 29587287
2018 Expression of RAD21 immunoreactivity in myenteric neurons of the human and mouse small intestine. Neurogastroenterology and motility 7 30069982
2015 Prenatal diagnosis and array comparative genomic hybridization characterization of interstitial deletions of 8q23.3-q24.11 and 8q24.13 associated with Langer-Giedion syndrome, Cornelia de Lange syndrome and haploinsufficiency of TRPS1, RAD21 and EXT1. Taiwanese journal of obstetrics & gynecology 7 26522117
2001 Human rad21 gene, hHR21(SP), is downregulated by hypoxia in human tumor cells. Biochemical and biophysical research communications 7 11243849
2024 NIPBL-mediated RAD21 facilitates tumorigenicity by the PI3K pathway in non-small-cell lung cancer. Communications biology 6 38378967
2023 The RNA Binding Protein HuR Promotes Neuronal Apoptosis in Rats with Spinal Cord Injury via the HDAC1/RAD21 Axis. Neuroscience 6 37164303
2022 A pan-cancer landscape of telomeric content shows that RAD21 and HGF alterations are associated with longer telomeres. Genome medicine 6 35227290
2019 Protein phosphatase 2A interacts with Verthandi/Rad21 to regulate mitosis and organ development in Drosophila. Scientific reports 6 31110215
1983 Syngeneic antiserum to Nulli SCC1 embryonal carcinoma cells recognizing surface antigens of embryonic cells. Journal of reproductive immunology 6 6644686

Missed literature

Know a paper Affinage missed for RAD21? Flag it for the maintainers and the community.

No submissions yet.