Affinage

TOP2A

DNA topoisomerase 2-alpha · UniProt P11388

Length
1531 aa
Mass
174.4 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TOP2A is a type IIA DNA topoisomerase that resolves topological constraints—catenanes, knots, and supercoils—by introducing transient double-strand breaks through a 5′-phosphotyrosyl covalent intermediate, functioning in DNA replication, transcription, chromatin remodeling, and chromosome segregation (PMID:1331984, PMID:8395511, PMID:20797631). Genome-wide mapping reveals two classes of TOP2A cleavage: CTCF-proximal sites and transcription-associated cleavage enriched at gene bodies, where TOP2A synergizes with BAF chromatin remodelers to convert facultative heterochromatin to accessible chromatin via decatenation (PMID:31649282, PMID:28385713, PMID:28250416). TOP2A is recruited to ultra-fine anaphase bridges by TOPBP1 and directed toward decatenation by condensin relocalization during anaphase; at stalled replication forks, ZATT-mediated SUMOylation of TOP2A recruits the translocase PICH to drive fork reversal (PMID:25762097, PMID:27716481, PMID:26686624, PMID:33296677). Trapped TOP2A–DNA cleavage complexes are resolved by complementary repair pathways including Tdp1- and TDP2-mediated phosphotyrosyl hydrolysis, ubiquitin- and VCP/p97-dependent proteasomal degradation, and SUMO-targeted translocase protection, while TOP2A protein stability is regulated by Bmi1/Ring1A ubiquitination and PTEN/OTUD3 deubiquitination (PMID:16751265, PMID:26421495, PMID:32587095, PMID:33941661, PMID:28552615, PMID:19956605, PMID:26657567).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1992 High

    Establishing that mammalian TOP2A is a functionally conserved type II topoisomerase: mouse TOP2A complemented a yeast top2 temperature-sensitive mutation and exhibited decatenation activity, confirming the catalytic mechanism is conserved across eukaryotes.

    Evidence Heterologous complementation of yeast top2-ts by mouse TOP2 cDNA with in vitro decatenation assay

    PMID:1331984

    Open questions at the time
    • Human TOP2A enzymatic parameters not directly measured in this study
    • No distinction between TOP2A and TOP2B functions
  2. 1993 High

    Identifying a drug-interaction domain within topoisomerase II: the top2-5 mutant mapped clustered point mutations that reduced amsacrine-stabilized cleavage and conferred drug resistance, defining a region critical for poison-stabilized cleavage complex formation.

    Evidence Purification of mutant Top2 enzyme with in vitro cleavage assays and drug sensitivity in yeast

    PMID:8395511

    Open questions at the time
    • Structural basis of drug-enzyme-DNA ternary complex not resolved
    • Generalizability to human TOP2A drug interaction not shown
  3. 2006 High

    Revealing how cells repair trapped Top2–DNA complexes: Tdp1 was shown to hydrolyze 5′-phosphotyrosyl bonds linking Top2-derived peptides to DNA, identifying the first enzymatic repair pathway for Top2-mediated DNA damage.

    Evidence In vitro enzymatic assay with recombinant Tdp1 on synthetic Top2 peptide-DNA substrates; genetic epistasis in yeast tdp1Δ mutants

    PMID:16751265

    Open questions at the time
    • Relative contribution of Tdp1 vs. proteasomal degradation pathways in human cells unclear
    • Whether Tdp1 acts on intact Top2 protein or requires prior proteolysis not resolved
  4. 2009 High

    Defining TOP2A's genome-wide binding landscape and its role in maintaining chromosome integrity: Top2 binds intergenic regions near transcribed genes in S phase and replication termination regions, where it prevents DNA breaks and genome rearrangements during fork fusion.

    Evidence Genome-wide ChIP-on-chip in S. cerevisiae with genetic analysis of top2 mutants showing γH2A accumulation and DNA breaks at Top2-bound loci

    PMID:19737516 PMID:20797631

    Open questions at the time
    • Whether the same intergenic binding pattern applies to human TOP2A
    • The precise topological substrate (supercoil vs. catenane) at each class of site was not distinguished
  5. 2009 High

    Identifying the ubiquitin-proteasome pathway as a regulator of trapped TOP2A complexes: Bmi1/Ring1A E3 ligase ubiquitinates TOP2A and promotes proteasomal degradation of drug-stabilized cleavage complexes, modulating drug sensitivity.

    Evidence In vitro ubiquitination with recombinant Bmi1/Ring1A; siRNA knockdown and small-molecule inhibition in human cells with drug sensitivity assays

    PMID:19956605

    Open questions at the time
    • Whether Bmi1/Ring1A ubiquitination is specific to trapped complexes or also regulates physiological TOP2A turnover
    • Lysine residue(s) on TOP2A targeted for ubiquitination not mapped
  6. 2011 Medium

    Demonstrating TOP2A is required continuously throughout mitosis including telophase, establishing that its function extends beyond metaphase decatenation.

    Evidence Stage-specific temperature-shift inactivation of top2-ts alleles during discrete mitotic stages in fission yeast

    PMID:21540296

    Open questions at the time
    • Precise topological substrate in telophase not identified
    • Whether the telophase requirement reflects catenane resolution or a distinct activity unclear
  7. 2015 High

    Discovering how TOP2A is recruited to ultra-fine anaphase bridges and how its stability is regulated: TOPBP1 directly recruits TOP2A to centromeric UFBs via its BRCT5 domain, while PTEN stabilizes TOP2A through the deubiquitinase OTUD3, linking TOP2A protein homeostasis to the decatenation checkpoint.

    Evidence Co-IP with domain mapping and TOPBP1 mutant dominant-negative phenotype; PTEN-OTUD3 deubiquitination assays with UFB scoring

    PMID:25762097 PMID:26657567

    Open questions at the time
    • Whether TOPBP1 activates TOP2A catalytic activity or merely provides localization
    • How PTEN-OTUD3 recognizes ubiquitinated TOP2A specifically
  8. 2016 High

    Revealing cell-cycle–regulated phosphorylation and condensin-directed decatenation: CDC7/DBF4 phosphorylates TOP2A at S1213/S1525 in early S phase to regulate centromeric recruitment timing, while condensin relocalizes from centromeres to chromosome arms in anaphase to direct Top2 toward decatenation, with sister chromatid catenanes forming independently of replication.

    Evidence Analog-sensitive kinase assay with MS phosphosite identification and mutagenesis; ChIP-seq of condensin and Top2 across the cell cycle with Polo kinase inhibition; 2D gel detection of SCIs

    PMID:26686624 PMID:27407105 PMID:27716481

    Open questions at the time
    • Whether S1213/S1525 phosphorylation affects TOP2A catalytic activity directly or only localization
    • The molecular mechanism by which condensin's supercoiling biases Top2 toward decatenation
  9. 2017 High

    Establishing TOP2A's role in chromatin accessibility and defining genome-wide cleavage site architecture: TOP2A synergizes with BAF remodelers to resolve facultative heterochromatin via decatenation, and nucleotide-resolution mapping revealed distinct CTCF-proximal and transcription-proximal cleavage classes, with cleavage enriched at gene bodies of highly transcribed loci relevant to therapy-related leukemia.

    Evidence ATAC-seq with genetic co-depletion of TOP2 and BAF subunits; genome-wide single-base cleavage mapping in human and yeast cells; etoposide treatment comparisons

    PMID:28250416 PMID:28385713 PMID:31649282

    Open questions at the time
    • Whether TOP2A-BAF synergy requires direct physical interaction
    • Structural basis for sequence preference at cleavage sites not resolved
  10. 2017 High

    Uncovering the SUMO-dependent pathway that protects Top2 from premature degradation: the SUMO-targeted translocase Rrp2/PICH competes with STUbL for SUMO chain binding on Top2, preventing excessive ubiquitination and exposure of concealed DNA breaks.

    Evidence Genome-wide screen in fission yeast; SUMO-binding and ubiquitination assays; genetic epistasis between rrp2Δ and STUbL mutants

    PMID:28552615

    Open questions at the time
    • Whether mammalian PICH performs the same protective function on TOP2A in unperturbed cells
    • How cells distinguish reversible from irreversible (abortive) Top2-DNA complexes
  11. 2018 High

    Identifying a naturally occurring dominant-negative TOP2A isoform and establishing TDP2 as a human repair enzyme for TOP2A cleavage complexes: the truncated TOP2α/90 isoform heterodimerizes with full-length TOP2α/170 to suppress etoposide-induced DNA breaks, while TDP2 depletion leads to accumulation of TOP2A cleavage complexes with pathway epistasis placing TDP2 in NHEJ.

    Evidence Co-IP of endogenous TOP2α/90 and TOP2α/170 with gain- and loss-of-function; TDP2 knockdown with TARDIS assay and DNA-PKcs inhibitor epistasis

    PMID:26421495 PMID:29514855

    Open questions at the time
    • Regulation of TOP2α/90 isoform expression under physiological conditions
    • Whether TDP2 acts on the intact full-length TOP2A-DNA complex or requires prior proteolysis
  12. 2020 Medium

    Defining the ubiquitin- and VCP/p97-dependent proteasomal processing of trapped TOP2A complexes: ubiquitin conjugation to TOP2A-DNA complexes is required for their conversion to protein-free DSBs, and VCP/p97 ATPase is epistatic with the proteasome in this pathway.

    Evidence E1 inhibitor and VCP/p97 inhibitor treatments with TARDIS assay quantification; siRNA depletion; immunoblot for ubiquitin-conjugated TOP2A-DNA complexes; comet assay

    PMID:32587095 PMID:33941661

    Open questions at the time
    • The specific E3 ligase acting on trapped TOP2A complexes in this context not identified
    • Direct physical interaction of VCP/p97 with ubiquitinated TOP2A not demonstrated
  13. 2020 High

    Revealing TOP2A's role at stalled replication forks: upon replication stress, TOP2A is recruited by SNF2-family translocases (HLTF, ZRANB3, SMARCAL1) and undergoes ZATT-mediated SUMOylation that recruits PICH, driving extensive fork reversal by resolving topological barriers.

    Evidence Co-IP of TOP2A with fork remodelers; SUMOylation assays; EM of fork structures; siRNA depletions of ZATT with defined fork reversal phenotype

    PMID:33296677

    Open questions at the time
    • Whether TOP2A catalytic activity (strand passage) is required or only its structural presence at forks
    • Structural basis of the ZATT-TOP2A-PICH complex not resolved
  14. 2021 High

    Establishing that transcription-associated TOP2A activity mediates G4 ligand cytotoxicity and that Cyclin A2/CDK1 phosphorylation of TOP2A at S1213 is required for S phase entry in vertebrates.

    Evidence Genetic screen identifying TOP2A as effector of G4 ligand-induced DNA damage with transcription inhibition epistasis; phosphomimetic TOP2A-S1213D rescue of cdk1/ccna2 mutant zebrafish

    PMID:33832859 PMID:34180392

    Open questions at the time
    • Whether G4-associated TOP2A cleavage is physiological or only relevant under drug perturbation
    • How S1213 phosphorylation mechanistically promotes S phase entry—whether through altered catalytic activity or protein-protein interactions
  15. 2022 Medium

    Linking TOP2A to neurodevelopment through chromatin regulation: embryonic Top2a inhibition dysregulates PRC2/H3K27me3-target genes enriched for autism-associated loci, and Ezh2 inhibition rescues Top2a-dependent social behavior deficits across zebrafish and mice.

    Evidence Drug screen and genetic mutation in zebrafish; prenatal Top2 inhibition in mice; transcriptomics; H3K27me3 ChIP; pharmacological rescue with Ezh2 inhibitor; behavioral assays

    PMID:36417527

    Open questions at the time
    • Whether TOP2A directly modifies chromatin at PRC2-target loci or acts indirectly through transcriptional changes
    • Human genetic evidence linking TOP2A to autism spectrum disorder not established
  16. 2023 High

    Revealing TOP2A's role in the abscission checkpoint: abortive TOP2A cleavage complexes on knotted DNA at chromatin bridges undergo proteasomal degradation to expose DSB ends, enabling Rad17-MRN-ATM-Chk2-INCENP signaling that delays cytokinetic abscission.

    Evidence Immunofluorescence of pathway components at chromatin bridges; TOP2A catalytic mutant; proteasome inhibitor epistasis; siRNA depletions with abscission checkpoint scoring

    PMID:37638884

    Open questions at the time
    • How abortive TOP2A complexes are distinguished from productive ones on knotted substrates
    • Whether this checkpoint operates in non-transformed primary cells

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions remain: the structural basis for TOP2A's recognition of distinct topological substrates (catenanes, knots, supercoils) in different genomic and cell-cycle contexts; the identity of all E3 ligases and deubiquitinases controlling TOP2A stability in specific pathways; and whether non-catalytic (scaffolding) functions of TOP2A contribute to its roles in chromatin remodeling, replication fork reversal, and gene regulation.
  • No structural model of TOP2A in complex with chromatin remodelers or fork reversal machinery
  • Comprehensive in vivo mapping of TOP2A post-translational modification crosstalk not performed
  • Relative contributions of TOP2A catalytic vs. scaffolding functions at each genomic context not delineated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 11 GO:0003677 DNA binding 4 GO:0016853 isomerase activity 2
Localization
GO:0005694 chromosome 6 GO:0005634 nucleus 3
Pathway
R-HSA-1640170 Cell Cycle 7 R-HSA-73894 DNA Repair 6 R-HSA-4839726 Chromatin organization 2 R-HSA-69306 DNA Replication 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
BMI1CDC7OTUD3PICHPTENTDP2TOPBP1ZATT
Complex memberships
TOP2A homodimerTOP2α/170–TOP2α/90 heterodimer

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Tyrosyl-DNA phosphodiesterase (Tdp1) can remove a peptide derived from yeast Top2 that is covalently bound to DNA by a 5' phosphotyrosyl linkage, and cells lacking Tdp1 are hypersensitive to Top2-targeting agents, establishing Tdp1 as a repair enzyme for Top2-mediated DNA damage. In vitro enzymatic assay with bacterially expressed Tdp1p and synthetic Top2-derived peptide-DNA substrate; genetic epistasis with tdp1 deletion mutants and Top2 poison sensitivity assays in yeast Proceedings of the National Academy of Sciences of the United States of America High 16751265
2010 Top2 DNA topoisomerase associates at chromosomal termination regions (TERs) in S phase and G2/M to facilitate replication fork fusion and prevent DNA breaks and genome rearrangements at these sites. Genomic chromatin immunoprecipitation (ChIP-on-chip) mapping of Top2 binding at TERs; genetic analysis with top2 mutants showing accumulation of DNA breaks; mechanistic epistasis with Rrm3 helicase Molecular cell High 20797631
2009 Top2 binds intergenic regions close to transcribed genes specifically in S phase, and Top2 is required to suppress chromosome fragility at these loci at the M-G1 transition; the HMG protein Hmo1 cooperates with Top2 in this architectural pathway. Genome-wide ChIP in S. cerevisiae; genetic analysis of top2 and hmo1 mutants showing accumulation of γH2A at Top2-bound loci; cell cycle fractionation Cell High 19737516
2009 The E3 ubiquitin ligase Bmi1/Ring1A ubiquitinates TOP2α (TOP2A) in vitro and promotes its drug-induced proteasomal degradation; silencing Bmi1 increases persistence of TOP2A-DNA cleavage complexes and enhances TOP2 drug efficacy. siRNA screen identifying Bmi1/Ring1A; in vitro ubiquitination assay with recombinant Bmi1/Ring1A and TOP2A; cellular overexpression and knockdown with drug sensitivity assays; small-molecule inhibitor of ubiquitin ligase activity PloS one High 19956605
2011 HuR RNA-binding protein binds the TOP2A 3'-UTR and increases TOP2A translation, while miR-548c-3p competes with HuR to repress TOP2A translation; their balance controls TOP2A protein abundance and doxorubicin efficacy. MS2-tagged RNA precipitation to identify miR-548c-3p; RNA immunoprecipitation (RIP) of HuR-TOP2A mRNA complex; siRNA knockdown of HuR; miRNA overexpression; doxorubicin DNA damage assays Molecular and cellular biology High 21768308
2015 TOPBP1 interacts with TOP2A via its C-terminal region (requiring BRCT domain 5 for UFB recruitment) and is required for TOP2A recruitment to ultra-fine anaphase bridges (UFBs); depletion of TOPBP1 or expression of a TOP2A-binding-deficient TOPBP1 mutant leads to accumulation of centromeric UFBs, phenocopying TOP2A depletion. Co-immunoprecipitation of endogenous TOPBP1 and TOP2A; domain mapping with TOPBP1 truncations; siRNA depletion; expression of TOPBP1 mutant defective in TOP2A binding; microscopic scoring of UFBs in mitosis Nature communications High 25762097
2015 PTEN physically associates with TOP2A, and PTEN promotes TOP2A protein stability through the deubiquitinase OTUD3, which inhibits TOP2A ubiquitination; loss of PTEN leads to downregulation of TOP2A, failure of the decatenation checkpoint, and ultra-fine bridge formation in anaphase. Co-immunoprecipitation of PTEN and TOP2A; OTUD3 deubiquitination assay; ubiquitination assay in PTEN-deficient cells; anaphase bridge scoring; G2 decatenation checkpoint assay Scientific reports High 26657567
2016 CDC7/DBF4 (DDK) kinase phosphorylates TOP2A at serine 1213 and serine 1525 in vitro; CDC7/DBF4 and TOP2A interact in cells mainly in early S phase; DDK down-regulation or S1213A/S1525A TOP2A mutations advance the timing of centromeric TOP2A recruitment in S phase. Analog-sensitive kinase assay (benzyl-thio-ATP) with recombinant CDC7/DBF4 and nuclear extracts; mass spectrometry identification of phosphosites; Co-IP of CDC7/DBF4 and TOP2A; site-directed mutagenesis; centromere ChIP with CDC7 inhibitor treatment Nucleic acids research High 27407105
2017 Topoisomerase II (TOP2, including TOP2A) synergizes with BAF (mSWI/SNF) chromatin remodeling complexes genome-wide to resolve facultative heterochromatin to accessible chromatin independently of transcription, through DNA (de-)catenation rather than torsional stress relief; TOP2 also participates in re-formation of facultative heterochromatin. In vivo chromatin accessibility assay; genetic depletion of TOP2 and TOP1; co-depletion with BAF subunits; ATAC-seq; rescue experiments distinguishing TOP1 from TOP2 activities; pluripotency factor recruitment assays Nature structural & molecular biology High 28250416
2016 Sister chromatid intertwines (SCIs/catenanes) are formed independently of DNA replication during G2/M by Top2-dependent concatenation of cohesed chromatids due to physical proximity; condensin provides bias toward Top2-mediated decatenation at anaphase onset, coinciding with condensin's DNA supercoiling activity. Genetic epistasis in S. cerevisiae using Top2 and cohesin mutants; 2D gel electrophoresis to detect SCIs; conditional depletion of Top2 at different cell cycle stages; condensin DNA supercoiling assay Molecular cell High 27716481
2019 A nucleotide-resolution map of Top2 DNA cleavage revealed two distinct fractions of human TOP2A activity: tightly localized CTCF-proximal cleavage and broadly distributed transcription-proximal cleavage correlated with gene length and expression; primary DNA sequence influences Top2 cleavage, distinguishing sites predisposed to form DSBs versus strand-biased SSBs induced by etoposide. High-throughput sequencing of Top2-linked DNA breaks at single-nucleotide resolution in S. cerevisiae and human genomes; strand-specific library preparation; comparison with ENCODE chromatin marks and CTCF binding data; etoposide treatment comparisons Nature communications High 31649282
2020 Upon replication stress, TOP2A is recruited to stalled replication forks in a manner dependent on the SNF2-family DNA translocases HLTF, ZRANB3, and SMARCAL1; TOP2A SUMOylation mediated by the SUMO E3 ligase ZATT then recruits the SUMO-targeted DNA translocase PICH; the ZATT-TOP2A-PICH axis drives extensive replication fork reversal by resolving topological barriers created by limited initial fork reversal. Co-immunoprecipitation of TOP2A with HLTF/ZRANB3/SMARCAL1 and PICH; SUMOylation assays; siRNA depletion of ZATT; electron microscopy of replication fork structures; proximity ligation assay at stalled forks Molecular cell High 33296677
2021 Transcription-associated TOP2A activity is a major effector of cytotoxicity induced by G4 ligands pyridostatin and CX-5461; both TOP2 activity and transcription account for G4 ligand-induced DNA break production; TOP1 counteracts clastogenic G4 ligand activity by limiting co-transcriptional G4 formation. Unbiased genetic screen identifying TOP2A as mediator of G4 ligand cytotoxicity; genetic depletion of TOP2A vs TOP1; TOP2 cleavage complex assays; transcription inhibition epistasis experiments eLife High 34180392
2017 Genome-wide TOP2A cleavage is enriched at transcribed gene bodies (biased toward distal regions), highly transcribed loci, and genes involved in treatment-related leukemia translocations; TOP2 poisons cause a proximal shift in cleavage cluster region distribution. High-throughput sequencing of TOP2A cleavage sites at single-base precision in human K562 cells; comparison with ENCODE chromatin marks; etoposide treatment experiments Genome research High 28385713
2015 Condensin relocalizes from centromeres to chromosome arms during anaphase in a Polo kinase-dependent manner, and this relocalization is required for Top2 recruitment to chromosome arms during anaphase to mediate chromosome segregation. ChIP-seq of condensin and Top2 in S. cerevisiae at defined cell cycle stages; Polo kinase inhibition; condensin temperature-sensitive mutant analysis; temporal correlation of condensin DNA-overwinding activity with Top2 recruitment Cell reports High 26686624
1993 The yeast top2-5 mutant encodes a topoisomerase II with clustered point mutations that reduce amsacrine-stabilized DNA cleavage activity in vitro and confer resistance to etoposide and amsacrine, identifying a domain important for interaction with anti-topoisomerase II drugs. Cloning and overexpression of top2-5 allele; purification of mutant protein; in vitro DNA cleavage assay with amsacrine and etoposide; sequencing of mutant allele; drug sensitivity in yeast The Journal of biological chemistry High 8395511
2019 MDM4 and TOP2A bind each other physically; the C-terminal region of TOP2A binds residues 188-238 of MDM4, stabilizing TOP2A protein and activating MDM4-p53 inhibitory interaction, resulting in mutual post-translational upregulation and enhanced cancer cell proliferation. Co-immunoprecipitation; domain mapping with deletion constructs; ubiquitination assay showing MDM4-dependent TOP2A protein stabilization; p53 binding and transcription assays; cell proliferation assays with knockdown and overexpression Molecular oncology Medium 30672125
2018 The C-terminally truncated TOP2α/90 isoform (786 aa, lacking the catalytic tyrosine-805) heterodimerizes with full-length TOP2α/170 and dominantly suppresses etoposide-induced DNA strand breaks and cytotoxicity, conferring etoposide resistance. Co-immunoprecipitation of endogenous TOP2α/90 and TOP2α/170; forced expression of TOP2α/90 in K562 cells; siRNA knockdown of TOP2α/90 in resistant K/VP.5 cells; comet assay and clonogenic survival assays Molecular pharmacology High 29514855
2018 TDP2 depletion in human cells leads to accumulation of increased Top2α cleavage complexes (Top2αcc) and altered kinetics of their removal after etoposide treatment, establishing TDP2 as a participant in TOP2A cleavage complex repair; TDP2 acts in canonical NHEJ and alternative end joining but not homologous recombination. TDP2 shRNA knockdown in human tumor cells; TARDIS (trapped in agarose DNA immunostaining) assay for Top2αcc quantification; γH2AX and pChk1 immunofluorescence; cytogenetics (chromosome breaks, SCE); micronucleus assay; DNA-PKcs inhibitor epistasis Mutation research High 26421495
2021 VCP/p97 AAA-ATPase is required for proteasomal degradation of drug-stabilized TOP2A-DNA covalent complexes; VCP/p97 inhibition prolongs accumulation of etoposide-induced TOP2A complexes and reduces γH2AX (DSBs), acting epistatically with the proteasomal pathway. VCP/p97 inhibitor treatment; TARDIS assay for TOP2A and TOP2B complex quantification; γH2AX immunofluorescence; epistasis with proteasome inhibitor MG132 Molecular pharmacology Medium 33941661
2020 Ubiquitination of TOP2A is required for liberation of etoposide-induced protein-free DSBs and proteasomal degradation of TOP2A-DNA complexes; inhibition or depletion of ubiquitin-activating enzymes reduces processing of TOP2A-DNA complexes, and etoposide-stabilized TOP2A-DNA complexes are conjugated to ubiquitin. Ubiquitin-activating enzyme (E1) inhibitor treatment; siRNA depletion; TARDIS assay for TOP2A and TOP2B complexes; immunoblot for ubiquitin conjugates on TOP2A-DNA complexes; comet assay for DSBs Molecular pharmacology Medium 32587095
2017 The fission yeast SUMO-targeted DNA translocase Rrp2 prevents excessive SUMOylation-dependent ubiquitination and proteasomal degradation of Top2, thereby protecting cells from exposure of concealed DNA breaks at Top2-DNA complexes; Rrp2 competes with the STUbL (SUMO-targeted ubiquitin ligase) for SUMO chain binding and displaces SUMOylated Top2 from DNA. Genome-wide screen for Top2 poison sensitivity; genetic analysis of rrp2Δ and STUbL mutants; SUMO-binding assay; Top2 SUMOylation and ubiquitination assays; Top2 protein stability measurements; DNA damage assays at Top2cc sites Molecular cell High 28552615
2021 TOP2A promotes G2-to-M cell cycle progression by inhibiting CHK1 phosphorylation and promotes EMT through Snail expression mediated by the p-ERK1/2/p-SMAD2 signaling pathway in hepatocellular carcinoma cells. TOP2A knockdown (shRNA) and overexpression in HCC cells; Western blot for p-CHK1, p-ERK1/2, p-SMAD2, Snail, E-cadherin, vimentin; cell cycle analysis; migration and invasion assays; correlation in 72 HCC specimens by IHC Bioengineered Low 34939898
2022 TOP2A promotes HCC cell cycle progression from G2 to M phase by inhibiting CHK1 phosphorylation, and promotes EMT; miR-144-3p directly targets the TOP2A 3'-UTR to suppress its expression. TOP2A knockdown and overexpression in HCC cells; cell cycle analysis; Western blot for CHK1 phosphorylation; Transwell invasion assay; luciferase reporter assay for miR-144-3p targeting of TOP2A 3'-UTR; in vivo xenograft Journal of Cancer Low 35069905
2023 TOP2A functions as a co-activator of β-catenin in cancer cells, and the TOP2A/β-catenin/YAP1 axis promotes HCC stemness by competitive binding of TOP2A to β-catenin, causing dissociation of β-catenin from YAP1. Co-immunoprecipitation of TOP2A and β-catenin; competitive binding assay showing TOP2A displaces YAP1 from β-catenin; single-cell RNA-seq and spatial transcriptomics; functional stemness and tumor growth assays iScience Medium 37275516
2022 Top2a promotes development of social behavior through an evolutionarily conserved pathway involving PRC2 and H3K27me3; embryonic Top2a inhibition down-regulates genes enriched for autism associations and PRC2 binding sites, and Ezh2 inhibition rescues social deficits caused by Top2 inhibition. Drug screen in zebrafish; Top2a mutation in zebrafish; prenatal Top2 inhibition in mice; transcriptomics of Top2a-regulated gene set; ChIP for H3K27me3; genetic rescue with Ezh2 inhibitor; behavioral assays Science advances Medium 36417527
2021 Cyclin A2/CDK1 phosphorylates Top2a at serine 1213, and this phosphorylation is required for S phase entry in zebrafish retinal cells; overexpression of the phosphomimetic TOP2A-S1213D rescues S phase entry and microphthalmia in cdk1 and ccna2 mutants. In silico analysis identifying Top2a as CDK1 substrate; genetic mutants (cdk1-/-, ccna2-/-, ccnb1-/-) in zebrafish; immunofluorescence for S1213 phosphorylation; overexpression of TOP2A-S1213D phosphomimetic; S phase entry quantification in retinal cells Journal of genetics and genomics High 33832859
2023 TOP2A forms abortive Top2-DNA cleavage complexes (Top2ccs) on knotted DNA at chromatin bridges; proteasomal degradation of Top2ccs is required for Rad17 localization to Top2-generated DSB ends, which recruits the MRN complex and activates ATM-Chk2-INCENP signaling to delay abscission and prevent chromatin breakage. Immunofluorescence for Top2α, Rad17, MRN, ATM/Chk2/INCENP at chromatin bridges; TOP2A catalytic mutant analysis; proteasome inhibitor treatment; siRNA depletions; functional abscission checkpoint scoring The Journal of cell biology High 37638884
2022 GINS1 physically interacts with TOP2A and promotes TOP2A protein stability through USP15-mediated deubiquitination, thereby driving glioma cell proliferation and migration. Co-immunoprecipitation of GINS1 and TOP2A; USP15 deubiquitination assay; siRNA knockdown of GINS1, TOP2A, USP15; cell proliferation and migration assays; orthotopic xenograft model iScience Medium 36065190
1992 Mouse DNA topoisomerase II (TOP2A ortholog) functionally complements yeast top2ts mutation and displays topoisomerase II enzymatic activity in yeast cells, confirming conservation of catalytic function. Complementation of temperature-sensitive yeast top2 mutation by mouse TOP2 cDNA under GAL1 promoter; enzymatic decatenation assay; immunological detection in yeast Nucleic acids research High 1331984
2024 CX-5461 induces TOP2α-dependent DNA damage preferentially localized at the ribosomal DNA (rDNA) promoter region; sensitivity to CX-5461 in B lymphoma cells is dependent on cellular TOP2α expression/activity. TOP2α expression manipulation (knockdown/overexpression); γH2AX and TOP2cc detection at rDNA loci by ChIP; comparison of DNA damage distribution vs canonical TOP2α poisons; mouse Eµ-Myc B lymphoma model Biomedicines Medium 39062087
2011 Top2 (DNA topoisomerase II) is continuously required throughout mitosis including telophase in fission yeast, as demonstrated by inactivation at discrete mitotic stages; Top2 requirement at telophase is distinct from that of condensin. Temperature-shift experiments using top2 ts alleles combined with cold-sensitive nda3-KM311 (β-tubulin) to inactivate Top2 at specific mitotic stages; chromosome segregation assays Journal of cell science Medium 21540296

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 Untangling the roles of TOP2A and TOP2B in transcription and cancer. Science advances 171 36322662
2009 TOP2A overexpression in hepatocellular carcinoma correlates with early age onset, shorter patients survival and chemoresistance. International journal of cancer 162 19003983
2006 Tyrosyl-DNA phosphodiesterase (Tdp1) participates in the repair of Top2-mediated DNA damage. Proceedings of the National Academy of Sciences of the United States of America 127 16751265
2010 Replication termination at eukaryotic chromosomes is mediated by Top2 and occurs at genomic loci containing pausing elements. Molecular cell 123 20797631
2008 Genomic analysis of the HER2/TOP2A amplicon in breast cancer and breast cancer cell lines. Laboratory investigation; a journal of technical methods and pathology 120 18332872
2017 TOP2A induces malignant character of pancreatic cancer through activating β-catenin signaling pathway. Biochimica et biophysica acta. Molecular basis of disease 111 29045811
2006 HER2, TOP2A, CCND1, EGFR and C-MYC oncogene amplification in colorectal cancer. Journal of clinical pathology 107 16882699
2009 Genome-organizing factors Top2 and Hmo1 prevent chromosome fragility at sites of S phase transcription. Cell 98 19737516
2011 Translational control of TOP2A influences doxorubicin efficacy. Molecular and cellular biology 86 21768308
2003 HER-2 and TOP2A coamplification in urinary bladder cancer. International journal of cancer 85 14566826
2019 A nucleotide resolution map of Top2-linked DNA breaks in the yeast and human genome. Nature communications 78 31649282
2018 Proliferation and invasion of colon cancer cells are suppressed by knockdown of TOP2A. Journal of cellular biochemistry 75 29761838
2009 The E3 ubiquitin-ligase Bmi1/Ring1A controls the proteasomal degradation of Top2alpha cleavage complex - a potentially new drug target. PloS one 74 19956605
2021 Transcription-associated topoisomerase 2α (TOP2A) activity is a major effector of cytotoxicity induced by G-quadruplex ligands. eLife 73 34180392
2017 TOP2 synergizes with BAF chromatin remodeling for both resolution and formation of facultative heterochromatin. Nature structural & molecular biology 73 28250416
2013 TOP2A is overexpressed and is a therapeutic target for adrenocortical carcinoma. Endocrine-related cancer 72 23533247
2015 TOPBP1 recruits TOP2A to ultra-fine anaphase bridges to aid in their resolution. Nature communications 70 25762097
1986 The complete nucleotide sequence of the structural gene TOP2 of yeast DNA topoisomerase II. The Journal of biological chemistry 69 3017975
2020 The ZATT-TOP2A-PICH Axis Drives Extensive Replication Fork Reversal to Promote Genome Stability. Molecular cell 65 33296677
1998 Structural organization of the human TOP2A and TOP2B genes. Gene 60 9795238
2019 Mutual regulation of MDM4 and TOP2A in cancer cell proliferation. Molecular oncology 55 30672125
2015 Predicting Anthracycline Benefit: TOP2A and CEP17-Not Only but Also. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 54 25897160
1993 The top2-5 mutant of yeast topoisomerase II encodes an enzyme resistant to etoposide and amsacrine. The Journal of biological chemistry 54 8395511
2006 Simultaneous amplification of HER-2 (ERBB2) and topoisomerase IIalpha (TOP2A) genes--molecular basis for combination chemotherapy in cancer. Current cancer drug targets 52 17100565
2018 The Inhibition of miR-144-3p on Cell Proliferation and Metastasis by Targeting TOP2A in HCMV-Positive Glioblastoma Cells. Molecules (Basel, Switzerland) 50 30544723
2023 EZH2-H3K27me3-mediated silencing of mir-139-5p inhibits cellular senescence in hepatocellular carcinoma by activating TOP2A. Journal of experimental & clinical cancer research : CR 49 38008711
2022 TOP2A promotes proliferation and metastasis of hepatocellular carcinoma regulated by miR-144-3p. Journal of Cancer 49 35069905
2011 Condensin phosphorylated by the Aurora-B-like kinase Ark1 is continuously required until telophase in a mode distinct from Top2. Journal of cell science 49 21540296
2003 TOP2A and HER-2 gene amplification in fine needle aspirates from breast carcinomas. Cytopathology : official journal of the British Society for Clinical Cytology 47 14632728
2019 Evodiamine-inspired dual inhibitors of histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) with potent antitumor activity. Acta pharmaceutica Sinica. B 46 32874829
2012 HER2 and TOP2A in high-risk early breast cancer patients treated with adjuvant epirubicin-based dose-dense sequential chemotherapy. Journal of translational medicine 44 22240029
2017 Genome-wide TOP2A DNA cleavage is biased toward translocated and highly transcribed loci. Genome research 43 28385713
2016 Physical Proximity of Sister Chromatids Promotes Top2-Dependent Intertwining. Molecular cell 43 27716481
2003 Topoisomerase IIalpha gene (TOP2A) amplification and deletion in cancer--more common than anticipated. Cytopathology : official journal of the British Society for Clinical Cytology 43 14632727
2009 Simultaneous detection of TOP2A and HER2 gene amplification by multiplex ligation-dependent probe amplification in breast cancer. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 40 19767729
2006 TOP2A and HER2 gene amplification as predictors of response to anthracycline treatment in breast cancer. Acta oncologica (Stockholm, Sweden) 40 16864174
2015 PTEN stabilizes TOP2A and regulates the DNA decatenation. Scientific reports 39 26657567
2020 LncRNA FAM230B Promotes Gastric Cancer Growth and Metastasis by Regulating the miR-27a-5p/TOP2A Axis. Digestive diseases and sciences 38 32910366
2015 TOP2A gene copy gain predicts response of epithelial ovarian cancers to pegylated liposomal doxorubicin: TOP2A as marker of response to PLD in ovarian cancer. Gynecologic oncology 38 26100858
1992 Characterization of cDNA encoding the mouse DNA topoisomerase II that can complement the budding yeast top2 mutation. Nucleic acids research 38 1331984
2024 Deubiquitinase USP7 stabilizes KDM5B and promotes tumor progression and cisplatin resistance in nasopharyngeal carcinoma through the ZBTB16/TOP2A axis. Cell death and differentiation 36 38287116
2013 The Arabidopsis oligopeptidases TOP1 and TOP2 are salicylic acid targets that modulate SA-mediated signaling and the immune response. The Plant journal : for cell and molecular biology 36 24004003
2023 Targeting long non-coding RNA MALAT1 reverses cancerous phenotypes of breast cancer cells through microRNA-561-3p/TOP2A axis. Scientific reports 33 37244966
2021 Type IIA topoisomerase (TOP2A) triggers epithelial-mesenchymal transition and facilitates HCC progression by regulating Snail expression. Bioengineered 33 34939898
2017 SUMO-Targeted DNA Translocase Rrp2 Protects the Genome from Top2-Induced DNA Damage. Molecular cell 32 28552615
2020 TOP2A Promotes Cell Migration, Invasion and Epithelial-Mesenchymal Transition in Cervical Cancer via Activating the PI3K/AKT Signaling. Cancer management and research 31 32547216
2024 TOP2A modulates signaling via the AKT/mTOR pathway to promote ovarian cancer cell proliferation. Cancer biology & therapy 30 38445610
2017 TOP2A, GGH, and PECAM1 are associated with hematogenous, lymph node, and peritoneal recurrence in stage II/III gastric cancer patients enrolled in the ACTS-GC study. Oncotarget 30 28915696
2015 Condensin Relocalization from Centromeres to Chromosome Arms Promotes Top2 Recruitment during Anaphase. Cell reports 30 26686624
2011 Expression of p53, Ki-67, E-cadherin, N-cadherin and TOP2A in triple-negative breast cancer. Anticancer research 30 21737670
2009 Aberrations of ERBB2 and TOP2A genes in breast cancer. Molecular oncology 30 19945923
2007 HER-2, TOP2A and chromosome 17 alterations in breast cancer. Pathology oncology research : POR 29 17922046
2004 Gene copy mapping of the ERBB2/TOP2A region in breast cancer. Genes, chromosomes & cancer 29 15034864
2022 GINS1 promotes the proliferation and migration of glioma cells through USP15-mediated deubiquitination of TOP2A. iScience 28 36065190
2016 A phase II study of Epirubicin in oxaliplatin-resistant patients with metastatic colorectal cancer and TOP2A gene amplification. BMC cancer 28 26867764
2016 Comparative evaluation of three proliferation markers, Ki-67, TOP2A, and RacGAP1, in bronchopulmonary neuroendocrine neoplasms: Issues and prospects. Oncotarget 28 27259241
2016 DDK dependent regulation of TOP2A at centromeres revealed by a chemical genetics approach. Nucleic acids research 28 27407105
2014 HER2 and TOP2A amplification in a hospital-based cohort of breast cancer patients: associations with patient and tumor characteristics. Breast cancer research and treatment 28 24682655
2020 Inhibition of topoisomerase IIA (Top2α) induces telomeric DNA damage and T cell dysfunction during chronic viral infection. Cell death & disease 26 32193368
2011 Expression analysis of TOP2A, MSH2 and MLH1 genes in MCF7 cells at different levels of etoposide resistance. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 25 22285073
2022 Top2a promotes the development of social behavior via PRC2 and H3K27me3. Science advances 24 36417527
2024 Muscone restores anoikis sensitivity in TMZ-resistant glioblastoma cells by suppressing TOP2A via the EGFR/Integrin β1/FAK signaling pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 22 38723526
2019 Promoter polymorphisms of TOP2A and ERCC1 genes as predictive factors for chemotherapy in non-small cell lung cancer patients. Cancer medicine 22 31797573
2018 Effect of TDP2 on the Level of TOP2-DNA Complexes and SUMOylated TOP2-DNA Complexes. International journal of molecular sciences 22 30011940
2022 TOP2A deficiency leads to human recurrent spontaneous abortion and growth retardation of mouse pre-implantation embryos. Molecular medicine (Cambridge, Mass.) 21 36585615
2020 Ribosomal protein S11 influences glioma response to TOP2 poisons. Oncogene 21 32528131
2017 TDP2, TOP2, and SUMO: what is ZATT about? Cell research 20 29160298
2016 Immunocytochemical study of TOP2A and Ki-67 in cervical smears from women under routine gynecological care. Journal of biomedical science 20 27175798
2022 Etoposide-induced DNA damage is increased in p53 mutants: identification of ATR and other genes that influence effects of p53 mutations on Top2-induced cytotoxicity. Oncotarget 19 35178190
2012 Sensitivity to TOP2 targeting chemotherapeutics is regulated by Oct1 and FILIP1L. PloS one 19 22900064
1998 Nuleclear extracts of Crithidia fasciculata contain a factor(s) that binds to the 5'-untranslated regions of TOP2 and RPA1 mRNAs containing sequences required for their cell cycle regulation. The Journal of biological chemistry 19 9726980
2021 Cyclin A2/cyclin-dependent kinase 1-dependent phosphorylation of Top2a is required for S phase entry during retinal development in zebrafish. Journal of genetics and genomics = Yi chuan xue bao 18 33832859
2005 Regulation of TOP2 by various abiotic stresses including cold and salinity in pea and transgenic tobacco plants. Plant & cell physiology 18 15879449
2024 Low level exposure to BDE-47 facilitates the development of prostate cancer through TOP2A/LDHA/lactylation positive feedback circuit. Environmental research 17 39362459
2023 cDCBLD2 mediates sorafenib resistance in hepatocellular carcinoma by sponging miR-345-5p binding to the TOP2A coding sequence. International journal of biological sciences 17 37781045
2015 Tyrosyl-DNA-phosphodiesterase I (TDP1) participates in the removal and repair of stabilized-Top2α cleavage complexes in human cells. Mutation research 17 26421495
2020 Implications of Topoisomerase (TOP1 and TOP2α) Expression in Patients With Breast Cancer. In vivo (Athens, Greece) 16 33144457
2008 Isolation and characterization of mAMSA-hypersensitive mutants. Cytotoxicity of Top2 covalent complexes containing DNA single strand breaks. The Journal of biological chemistry 16 18723844
2024 CX-5461 Preferentially Induces Top2α-Dependent DNA Breaks at Ribosomal DNA Loci. Biomedicines 15 39062087
2023 Potential Signature Therapeutic Biomarkers TOP2A, MAD2L1, and CDK1 in Colorectal Cancer: A Systems Biomedicine-Based Approach. Biochemical genetics 15 37884851
2022 TOP2A deficit-induced abnormal decidualization leads to recurrent implantation failure via the NF-κB signaling pathway. Reproductive biology and endocrinology : RB&E 15 36138481
2006 Analysis of ERBB2 and TOP2A gene status using fluorescence in situ hybridization versus immunohistochemistry in localized breast cancer. Neoplasma 15 17013533
2023 Striking efficacy of a vaccine targeting TOP2A for triple-negative breast cancer immunoprevention. NPJ precision oncology 14 37880313
2022 Knockdown of NUSAP1 inhibits cell proliferation and invasion through downregulation of TOP2A in human glioblastoma. Cell cycle (Georgetown, Tex.) 14 35532155
2021 Circ‑TOP2A acts as a ceRNA for miR‑346 and contributes to glioma progression via the modulation of sushi domain‑containing 2. Molecular medicine reports 14 33537815
2020 Individualized chemotherapy guided by the expression of ERCC1, RRM1, TUBB3, TYMS and TOP2A genes versus classic chemotherapy in the treatment of breast cancer: A comparative effectiveness study. Oncology letters 14 33240427
2019 Novel Deazaflavin Analogues Potently Inhibited Tyrosyl DNA Phosphodiesterase 2 (TDP2) and Strongly Sensitized Cancer Cells toward Treatment with Topoisomerase II (TOP2) Poison Etoposide. Journal of medicinal chemistry 14 30998359
2019 Spica Prunellae Extract Enhances Fluorouracil Sensitivity of 5-Fluorouracil-Resistant Human Colon Carcinoma HCT-8/5-FU Cells via TOP2α and miR-494. BioMed research international 14 31662984
2023 RAD54L2 counters TOP2-DNA adducts to promote genome stability. Science advances 13 38055822
2021 TOP2A/MCM2, p16INK4a, and cyclin E1 expression in liquid-based cytology: a biomarkers panel for progression risk of cervical premalignant lesions. BMC cancer 13 33413211
2021 MiR-599 targeting TOP2A inhibits the malignancy of bladder cancer cells. Biochemical and biophysical research communications 13 34284141
2020 The Indenoisoquinoline LMP517: A Novel Antitumor Agent Targeting both TOP1 and TOP2. Molecular cancer therapeutics 13 32430490
2020 Neochlorogenic acid enhances the antitumor effects of pingyangmycin via regulating TOP2A. Molecular medicine reports 13 33355372
2018 The Novel C-terminal Truncated 90-kDa Isoform of Topoisomerase IIα (TOP2α/90) Is a Determinant of Etoposide Resistance in K562 Leukemia Cells via Heterodimerization with the TOP2α/170 Isoform. Molecular pharmacology 13 29514855
2023 Chalcone Derivative CX258 Suppresses Colorectal Cancer via Inhibiting the TOP2A/Wnt/β-Catenin Signaling. Cells 12 37048139
2023 CD168+ macrophages promote hepatocellular carcinoma tumor stemness and progression through TOP2A/β-catenin/YAP1 axis. iScience 12 37275516
2023 The abscission checkpoint senses chromatin bridges through Top2α recruitment to DNA knots. The Journal of cell biology 12 37638884
2021 A Role for VCP/p97 in the Processing of Drug-Stabilized TOP2-DNA Covalent Complexes. Molecular pharmacology 12 33941661
2003 Light-mediated regulation defines a minimal promoter region of TOP2. Nucleic acids research 12 12954761
2020 Small Molecule Inhibitors Confirm Ubiquitin-Dependent Removal of TOP2-DNA Covalent Complexes. Molecular pharmacology 10 32587095