TOP2B

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0003918 DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) activity	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation based on phylogenetic inference from multiple orthologs across diverse species. TOP2B is a well-characterized type II topoisomerase that catalyzes ATP-dependent double-strand DNA breaks, strand passage, and religation. The deep research extensively documents this core enzymatic function [PMID:10684600, PMID:21778401]. UniProt confirms EC 5.6.2.2 based on direct experimental evidence. Reason: This is the core molecular function of TOP2B. IBA annotation is well-supported by the phylogenetic context and extensive experimental evidence from multiple publications demonstrating type II topoisomerase activity. Supporting Evidence: file:human/TOP2B/TOP2B-deep-research-perplexity.md TOP2B belongs to the type II topoisomerase family, a group of evolutionary conserved enzymes that catalyze topological changes in DNA by introducing transient double-strand breaks. PMID:10684600 Mutagenesis of E477 or K505 in the B' domain of human topoisomerase II beta increases the requirement for magnesium ions during strand passage. file:human/TOP2B/TOP2B-deep-research-falcon.md DNA topoisomerase IIβ (TOP2B) is a type II topoisomerase that changes DNA topology by an ATP-dependent strand-passage reaction. Mechanistically, one duplex DNA segment (G-DNA, gate) is transiently cleaved to create an enzyme-bridged break, and a second duplex (T-DNA, transported) is passed through; the G-DNA is then religated, and ATP hydrolysis resets the enzyme cycle.
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for nuclear localization is well-supported by extensive experimental evidence showing TOP2B is a nuclear protein. Multiple IDA annotations from PMID:9155056, PMID:9049244, and PMID:17567603 confirm nuclear localization. Reason: Nuclear localization is the primary subcellular location for TOP2B, where it performs its core functions in transcription and chromatin organization. Extensively supported by experimental evidence. Supporting Evidence: PMID:9155056 The distribution and expression of the two isoforms of DNA topoisomerase II in normal and neoplastic human tissues.
GO:0000819 sister chromatid segregation	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: IBA annotation based on phylogenetic inference. While type II topoisomerases generally function in chromosome segregation, TOP2B (unlike TOP2A) diffuses into the cytosol during mitosis and is not associated with condensed chromosomes [PMID:9049244]. TOP2A is the primary isoform involved in mitotic chromosome segregation in mammals. Reason: TOP2B may contribute to sister chromatid segregation in some contexts based on phylogenetic inference from yeast and other organisms with single TOP2 enzymes. However, in mammalian cells, TOP2A is the primary isoform for mitotic functions while TOP2B is released from chromatin during mitosis. This annotation is not incorrect phylogenetically but does not represent a core function in humans. Supporting Evidence: PMID:9049244 Topoisomerase IIβ diffused completely into the cytosol and was not detectable at all in the condensed chromatin (Fig. 4
GO:0000712 resolution of meiotic recombination intermediates	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: IBA annotation based on phylogenetic inference, primarily from fission yeast where the single TOP2 enzyme functions in meiotic recombination. Evidence for TOP2B specifically in mammalian meiotic recombination resolution is limited. TOP2A may be more relevant for meiotic functions. Reason: The annotation is phylogenetically reasonable but represents inference rather than direct evidence for TOP2B function in human meiotic recombination. Cannot definitively accept or remove without more specific evidence. Supporting Evidence: GO_REF:0000033 Annotation inferences using phylogenetic trees from GO_Central.
GO:0000166 nucleotide binding	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation from UniProtKB keyword mapping. TOP2B binds ATP through its N-terminal ATPase domain. This is a valid but overly general annotation - ATP binding (GO:0005524) is more specific and informative. Reason: Correct but general annotation. TOP2B requires ATP for its catalytic cycle. More specific ATP binding annotation is also present. Supporting Evidence: file:human/TOP2B/TOP2B-uniprot.txt UniProtKB-KW:KW-0547 (nucleotide binding) mapped to GO term.
GO:0003677 DNA binding	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation from combined automated methods. TOP2B binds DNA as part of its core catalytic mechanism - it binds two DNA duplexes, cleaves one, and passes the other through the break. DNA binding is essential for its topoisomerase activity. Reason: DNA binding is fundamental to TOP2B function. The enzyme binds DNA substrates, forms covalent phosphotyrosyl intermediates with DNA, and requires DNA binding for strand passage. Well-supported by structural studies [PMID:21778401]. Supporting Evidence: file:human/TOP2B/TOP2B-deep-research-perplexity.md First, the enzyme binds to DNA as a homodimer, with each monomer of the dimer responsible for cleaving one strand of the duplex DNA.
GO:0003682 chromatin binding	IEA GO_REF:0000117	ACCEPT	Summary: IEA annotation from ARBA machine learning models. TOP2B binds chromatin at specific genomic loci including promoters, enhancers, and TAD boundaries. Experimental evidence from PMID:9049244 directly demonstrates chromatin binding by IDA. Recent 2024 work using TOP2Bcc-seq in neurons (PMID:38377005) further showed that catalytically engaged TOP2B is relatively depleted at promoters/TSSs and enriched across gene bodies in active chromatin states, refining (but not contradicting) prior occupancy data. Reason: Chromatin binding is well-established for TOP2B. The enzyme shows preferential binding to promoters and enhancers of active genes and to TAD boundaries with CTCF and cohesin, with catalytic engagement enriched within gene bodies of actively transcribed loci. Supporting Evidence: PMID:9049244 Cell cycle-coupled relocation of types I and II topoisomerases and modulation of catalytic enzyme activities. file:human/TOP2B/TOP2B-deep-research-falcon.md Distribution: TOP2B catalytic engagement is relatively depleted at promoters/TSSs and enriched across gene bodies and active chromatin/transcription states. These results support a model where TOP2B's catalytic function is frequently deployed within transcribed regions to manage topological constraints rather than being limited to promoter-localized binding. PMID:38377005 Promoters with high RNA polymerase II occupancy show elevated TOP2B chromatin immunoprecipitation sequencing signals but low TOP2Bccs, indicating that TOP2B catalytic engagement is curtailed at active promoters.
GO:0003916 DNA topoisomerase activity	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation from UniProt keyword mapping. This is a parent term of GO:0003918 (DNA topoisomerase type II activity). While correct, it is less specific than the type II topoisomerase annotation. Reason: Correct annotation at a general level. The more specific type II topoisomerase annotation is also present. Both are valid as TOP2B is indeed a DNA topoisomerase. Supporting Evidence: file:human/TOP2B/TOP2B-uniprot.txt UniProtKB-KW:KW-0799 (topoisomerase) mapped to GO term.
GO:0003918 DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) activity	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation from combined automated methods including InterPro domain mapping and sequence similarity. This is the core molecular function of TOP2B and is extensively supported by experimental evidence including IDA from PMID:10684600 and IMP from PMID:31409799. Reason: Core molecular function. IEA annotation is consistent with the extensive experimental evidence for type II topoisomerase activity. Supporting Evidence: PMID:10684600 Mutagenesis of E477 or K505 in the B' domain of human topoisomerase II beta increases the requirement for magnesium ions during strand passage.
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation from domain-based inference. TOP2B has an N-terminal ATPase domain that binds and hydrolyzes ATP. ATP binding is essential for the conformational changes required for strand passage during the catalytic cycle. Reason: ATP binding is a core feature of type II topoisomerases. The N-terminal ATPase domain binds ATP and hydrolysis drives the catalytic cycle. Well-supported by structural studies and biochemistry. Supporting Evidence: file:human/TOP2B/TOP2B-deep-research-perplexity.md The ATP hydrolysis catalyzed by the N-terminal ATPase domain of TOP2B is essential for the conformational changes required for strand passage. file:human/TOP2B/TOP2B-deep-research-falcon.md The N-terminal ATPase domain has a Bergerat/GHKL fold; E103 acts as a catalytic base for ATP hydrolysis (E103A abolishes ATP hydrolysis). Reported ATPase kinetic parameters (construct-dependent): e.g., Km ~0.115 mM for ATP for a 45-444 ATPase-domain construct. PMID:35660158 Human topoisomerase II beta (TOP2B) modulates DNA topology using energy from ATP hydrolysis. PMID:35660158 Mutagenesis demonstrated residue E103 as essential for ATP hydrolysis in TOP2B.
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for nuclear localization from automated methods. Redundant with IBA and multiple IDA annotations but correct. Reason: Nuclear localization is well-established for TOP2B. Multiple experimental studies confirm this localization. Supporting Evidence: PMID:9155056 The distribution and expression of the two isoforms of DNA topoisomerase II in normal and neoplastic human tissues. file:human/TOP2B/TOP2B-deep-research-falcon.md TOP2B is primarily a nuclear enzyme. Structural work on human TOP2B states that the C-terminal domain contains nuclear localization signals and many phosphorylation sites, consistent with nuclear chromatin-associated function.
GO:0005654 nucleoplasm	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation from UniProt subcellular location vocabulary mapping. Nucleoplasm localization is well-supported by experimental evidence showing TOP2B in the nucleoplasm but excluded from nucleoli in interphase [PMID:9049244]. Reason: Nucleoplasm is the primary subnuclear localization for TOP2B during interphase when it is catalytically active. Supported by multiple IDA annotations. Supporting Evidence: PMID:9049244 Topoisomerase IIβ exhibited a patchy reticular distribution, markedly different from topoisomerase IIα. It was most dense in peri-nucleolar regions, but it was clearly always excluded from the interior of the nucleoli (Fig. 4 file:human/TOP2B/TOP2B-deep-research-falcon.md TOP2B is primarily a nuclear enzyme. Structural work on human TOP2B states that the C-terminal domain contains nuclear localization signals and many phosphorylation sites, consistent with nuclear chromatin-associated function.
GO:0006259 DNA metabolic process	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation from InterPro domain mapping. This is a very general biological process term. TOP2B is involved in DNA topology changes during transcription - the more specific term GO:0006265 (DNA topological change) is more appropriate. Reason: While very general, this annotation is technically correct as TOP2B is involved in DNA metabolic processes through its topoisomerase activity. More specific annotations also present. Supporting Evidence: file:human/TOP2B/TOP2B-uniprot.txt InterPro:IPR013758 mapping to DNA metabolic process.
GO:0006265 DNA topological change	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation from automated methods. DNA topological change is the direct outcome of TOP2B catalytic activity - relieving supercoiling and decatenating DNA. Also supported by IDA from PMID:10684600. Reason: This is the core biological process in which TOP2B participates. Type II topoisomerases change DNA topology by introducing transient double-strand breaks and passing DNA through them. Supporting Evidence: PMID:10684600 A type II topoisomerase is essential for decatenating DNA replication products, and it accomplishes this task by passing one DNA duplex through a transient break in a second duplex. file:human/TOP2B/TOP2B-deep-research-falcon.md Current evidence supports TOP2B as a major regulator of transcription-associated topology. In neurons, TOP2B helps resolve torsional stress generated by transcription and is linked to regulated gene-expression programs, including immediate early/stress response transcription.
GO:0016853 isomerase activity	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation from UniProt keyword mapping. Topoisomerases are classified as isomerases (EC 5.x.x.x) that change DNA topology without changing nucleotide sequence. This is a very general molecular function parent term. Reason: Technically correct as type II topoisomerases are classified as isomerases (EC 5.6.2.2). More specific topoisomerase annotations are also present and more informative. Supporting Evidence: file:human/TOP2B/TOP2B-uniprot.txt EC=5.6.2.2 classification as isomerase.
GO:0045870 positive regulation of single stranded viral RNA replication via double stranded DNA intermediate	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: IEA annotation from ARBA machine learning models. This refers to HIV-1 replication where TOP2 activity has been implicated. IMP evidence from PMID:16712776 supports this annotation. Reason: This represents a role of TOP2B in viral infection rather than a core cellular function. The IMP annotation from PMID:16712776 provides experimental support, but this is a host-pathogen interaction rather than core gene function. Supporting Evidence: PMID:16712776 It has been shown that Topoisomerase II activity is required for HIV-1 replication and the enzyme is phosphorylated during early time points of HIV-1 replication.
GO:0046872 metal ion binding	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation from UniProt keyword mapping. TOP2B requires divalent metal ions (Mg2+, Mn2+, or Ca2+) as cofactors for its catalytic activity. Two Mg2+ ions bind per subunit. Reason: Metal ion binding is essential for TOP2B catalysis. The TOPRIM domain coordinates Mg2+ ions required for DNA cleavage and religation. Well-documented in structural and biochemical studies [PMID:21778401, PMID:10684600]. Supporting Evidence: PMID:10684600 Mutagenesis of E477 or K505 in the B' domain of human topoisomerase II beta increases the requirement for magnesium ions during strand passage. file:human/TOP2B/TOP2B-uniprot.txt Binds two Mg(2+) per subunit. The magnesium ions form salt bridges with both the protein and the DNA.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: IPI annotation from large-scale interactome study showing interaction with PIAS4. Generic protein binding term is less informative than specifying the actual binding partner and functional context. Reason: Generic protein binding annotation from high-throughput study. While TOP2B does interact with PIAS4 (SUMO E3 ligase), the term protein binding is uninformative. More specific annotations describing the functional context would be preferable. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0001764 neuron migration	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation transferred from mouse ortholog via Ensembl Compara. TOP2B is highly expressed in neurons and required for neuronal development and survival. Mouse knockout studies show neurological defects. The deep research confirms TOP2B importance in neuronal function and development. Reason: TOP2B plays important roles in neuronal development and survival, and mouse knockouts show neurological phenotypes. However, neuron migration is a downstream phenotypic consequence rather than a direct molecular function. The annotation is based on mouse model inference. Supporting Evidence: file:human/TOP2B/TOP2B-deep-research-perplexity.md The critical importance of TOP2B for neuronal survival is demonstrated by the severe phenotype of TOP2B knockout mice, which die during embryonic or early postnatal development with severe neurological abnormalities.
GO:0007409 axonogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation transferred from mouse ortholog. TOP2B is important for neuronal development in mice, but axonogenesis represents a downstream developmental phenotype rather than a direct function of TOP2B. Reason: While TOP2B is essential for neuronal development and survival, axonogenesis is a downstream developmental process. This annotation represents a phenotypic consequence in mouse models rather than direct molecular function. Supporting Evidence: GO_REF:0000107 Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara.
GO:0030183 B cell differentiation	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation from ortholog transfer. This is strongly supported by the IMP annotations from PMID:31409799 and PMID:32128574 demonstrating that TOP2B mutations cause B cell immunodeficiency in humans and B cell developmental defects in mice. Reason: B cell differentiation is a well-documented function of TOP2B. Human mutations in TOP2B cause BILU syndrome with complete absence of peripheral B cells. Mouse studies confirm requirement for B cell development. This is a core function supported by both human genetic and mouse knockout evidence. Supporting Evidence: PMID:31409799 TOP2B encodes a type II topoisomerase, an essential gene required to alleviate topological stress during DNA replication and gene transcription, with no previously known role in B cell development.
GO:0030900 forebrain development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation from mouse ortholog transfer. TOP2B knockout mice have severe neurological defects including forebrain developmental abnormalities. However, this represents a phenotypic consequence rather than a direct molecular function. Reason: TOP2B is essential for neuronal development and survival. Forebrain development defects in knockout mice are a downstream consequence of TOP2B's role in transcription of long neuronal genes. This is a phenotypic annotation rather than direct function. Supporting Evidence: file:human/TOP2B/TOP2B-deep-research-perplexity.md The critical importance of TOP2B for neuronal survival is demonstrated by the severe phenotype of TOP2B knockout mice, which die during embryonic or early postnatal development with severe neurological abnormalities.
GO:0043021 ribonucleoprotein complex binding	IEA GO_REF:0000107	UNDECIDED	Summary: IEA annotation from rat ortholog transfer. TOP2B does interact with RNA through its C-terminal domain, and this RNA binding is involved in nucleolar localization under ATP depletion conditions. However, RNP complex binding per se is not well characterized. Reason: While TOP2B has RNA binding capability through its CRD domain, specific ribonucleoprotein complex binding has not been well characterized experimentally for human TOP2B. The annotation is based on rat ortholog inference without direct human evidence. Supporting Evidence: file:human/TOP2B/TOP2B-deep-research-perplexity.md The molecular basis for ATP-dependent nucleolar localization involves a specific 50-residue region in the C-terminal domain of TOP2B termed the catalytic requirement domain (CRD). This domain mediates the interaction between TOP2B and cellular RNA.
GO:0070301 cellular response to hydrogen peroxide	IEA GO_REF:0000107	UNDECIDED	Summary: IEA annotation from rat ortholog transfer. Response to oxidative stress and hydrogen peroxide may involve TOP2B but direct evidence for human TOP2B in this process is limited. Reason: Annotation is based on ortholog transfer without direct human evidence. Cannot assess without access to the original rat experimental data. Supporting Evidence: GO_REF:0000107 Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara.
GO:0071318 cellular response to ATP	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation from rat ortholog transfer. TOP2B does respond to cellular ATP levels - it relocates from nucleoplasm to nucleolus when ATP is depleted. This is a regulatory mechanism for TOP2B activity. Reason: TOP2B subcellular localization is regulated by ATP levels. The enzyme relocates to the nucleolus during ATP depletion and returns to the nucleoplasm when ATP is restored. This represents a genuine response to ATP levels [deep research]. Supporting Evidence: file:human/TOP2B/TOP2B-deep-research-perplexity.md This regulated nucleolar-nucleoplasmic shuttling is controlled by the cellular energy status, particularly the levels of adenosine triphosphate (ATP). When ATP levels are depleted, TOP2B rapidly accumulates in the nucleolus.
GO:0090398 cellular senescence	IEA GO_REF:0000107	UNDECIDED	Summary: IEA annotation from rat ortholog transfer. Some evidence suggests TOP2B may be involved in aging-related processes. The deep research mentions emerging evidence for TOP2B in aging but this is not well-established. Reason: Emerging evidence links TOP2B to aging processes but the connection is not well-characterized experimentally. Cannot definitively accept or reject without more direct evidence. Supporting Evidence: file:human/TOP2B/TOP2B-deep-research-perplexity.md Emerging evidence suggests that TOP2B function may play a role in aging processes and cellular aging.
GO:2001034 positive regulation of double-strand break repair via nonhomologous end joining	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation from rat ortholog transfer. TOP2B-induced DSBs at immediate early gene promoters are repaired by NHEJ, and NHEJ factors are recruited to sites of TOP2B-mediated breaks. However, this annotation suggests TOP2B positively regulates NHEJ, which may be an overinterpretation. Reason: TOP2B generates DSBs that are repaired by NHEJ, and there is functional coupling between TOP2B activity and NHEJ at IEG promoters. However, whether TOP2B directly regulates NHEJ activity versus simply generating substrates for NHEJ repair is unclear. The annotation may conflate substrate provision with regulation. Supporting Evidence: file:human/TOP2B/TOP2B-deep-research-perplexity.md These breaks are transient in nature and are rapidly repaired through the non-homologous end joining (NHEJ) pathway. The recruitment of NHEJ factors including DNA-PKcs, KU70, KU80, and DNA ligase IV to the promoters of activated IEGs suggests that these DNA repair factors participate in the transcriptional activation process.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: IDA annotation from HPA immunofluorescence curation. Nucleoplasm is the primary subnuclear localization for TOP2B during interphase. Well-supported by multiple studies. Reason: Nucleoplasm localization is well-established by direct immunofluorescence studies. TOP2B is found throughout the nucleoplasm but excluded from nucleoli during interphase. Supporting Evidence: GO_REF:0000052 Gene Ontology annotation based on curation of immunofluorescence data.
GO:0005515 protein binding	IPI PMID:10473615 Using a biochemical approach to identify the primary dimeriz...	MARK AS OVER ANNOTATED	Summary: IPI annotation showing interaction with TOP2A. This publication is about identifying dimerization regions in TOP2A, but TOP2B was noted to interact. TOP2B forms homodimers and can form heterodimers with TOP2A. Reason: Generic protein binding annotation. While TOP2B does interact with TOP2A (and itself as homodimer), the term is uninformative. More specific annotation of homodimer formation or TOP2A interaction would be preferable. Supporting Evidence: PMID:10473615 Using a biochemical approach to identify the primary dimerization regions in human DNA topoisomerase IIalpha.
GO:0005515 protein binding	IPI PMID:11062478 Histone deacetylase interacts directly with DNA topoisomeras...	MODIFY	Summary: IPI annotation showing interaction with HDAC1 and HDAC2. This is a specific and biologically relevant interaction - HDACs interact with and modify TOP2 activity, and this interaction has functional consequences. Reason: The interaction with HDAC1/HDAC2 is real and functionally important, but generic protein binding is uninformative. A more specific annotation like histone deacetylase binding would be more appropriate. Proposed replacements: histone deacetylase binding Supporting Evidence: PMID:11062478 Histone deacetylase interacts directly with DNA topoisomerase II.
GO:0005515 protein binding	IPI PMID:11136718 Deacetylase activity associates with topoisomerase II and is...	MARK AS OVER ANNOTATED	Summary: IPI annotation for interaction with HDAC1 in context of etoposide-induced apoptosis. Duplicate with PMID:11062478 annotation but different reference. Reason: Duplicate protein binding annotation for HDAC interaction. The HDAC-TOP2 interaction is valid but generic protein binding is uninformative. Supporting Evidence: PMID:11136718 Deacetylase activity associates with topoisomerase II and is necessary for etoposide-induced apoptosis.
GO:0005515 protein binding	IPI PMID:16611985 Protein kinase C delta activates topoisomerase IIalpha to in...	MARK AS OVER ANNOTATED	Summary: IPI annotation showing interaction with PKC delta (PRKCD). The publication is primarily about TOP2A but may include TOP2B data. PKC phosphorylation regulates TOP2 activity. Reason: Generic protein binding annotation. The PKC delta interaction and phosphorylation is functionally relevant but the GO term is uninformative. Supporting Evidence: PMID:16611985 Protein kinase C delta activates topoisomerase IIalpha to induce apoptotic cell death in response to DNA damage.
GO:0005515 protein binding	IPI PMID:17567603 Nuclear interactions of topoisomerase II alpha and beta with...	MODIFY	Summary: IPI annotation showing interaction with PLSCR1 (phospholipid scramblase 1). This is a specific interaction with functional consequences - PLSCR1 increases TOP2 decatenation activity. Reason: The PLSCR1 interaction is specific and functionally relevant. Generic protein binding should be replaced with more specific term if available, or retained as IPI with specific with/from. Proposed replacements: protein binding Supporting Evidence: PMID:17567603 Nuclear interactions of topoisomerase II alpha and beta with phospholipid scramblase 1.
GO:0003918 DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) activity	IMP PMID:31409799 Mutations in topoisomerase IIβ result in a B cell immunodefi...	ACCEPT	Summary: IMP annotation from study of human TOP2B mutations causing B cell immunodeficiency. Patient mutations showed reduced enzymatic activity in biochemical assays. This provides direct evidence that TOP2B has type II topoisomerase activity and that this activity is functionally important. Reason: Strong experimental evidence from mutant phenotype studies in humans. Patient mutations reduce enzymatic activity >10-fold and cause dominant negative effects on wild-type enzyme. Directly demonstrates functional type II topoisomerase activity. Supporting Evidence: PMID:31409799 patient mutations in TOP2B have a dominant negative effect on enzyme function, resulting in defective proliferation, survival of B-2 cells, causing a block in B cell development, and impair humoral function in response to immunization.
GO:0030183 B cell differentiation	IMP PMID:31409799 Mutations in topoisomerase IIβ result in a B cell immunodefi...	ACCEPT	Summary: IMP annotation from human genetic study showing that TOP2B mutations cause complete absence of peripheral B cells. Patients have a block at early B cell development with no CD19+ B cell precursors in bone marrow. Reason: Direct human genetic evidence that TOP2B is required for B cell differentiation. Mutations cause complete B cell immunodeficiency (BILU syndrome) with developmental block at early B cell stage. This is a core function of TOP2B. Supporting Evidence: PMID:31409799 severe hypogammaglobulinemia, and absent CD19+ B cells, but had normal T-cell responses to mitogens.
GO:0003918 DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) activity	IMP PMID:32128574 Topoisomerase 2β mutation impairs early B-cell development.	ACCEPT	Summary: IMP annotation from study of TOP2B mutation causing B cell developmental defect. Confirms that TOP2B mutations affecting the TOPRIM domain impair enzyme function and cause B cell deficiency. Reason: Additional IMP evidence supporting type II topoisomerase activity. Mutation in TOPRIM domain causes functional impairment and B cell developmental block. Supporting Evidence: PMID:32128574 Recently, other dominant mutations affecting the TOPRIM domain of TOP2B have been shown to cause Hoffman syndrome that is characterized by B cell deficiency, limb abnormalities and facial dysmorphism 11 ( Supplemental Tables 1 and 2 ).
GO:0030183 B cell differentiation	IMP PMID:32128574 Topoisomerase 2β mutation impairs early B-cell development.	ACCEPT	Summary: IMP annotation confirming TOP2B role in B cell development. This publication confirms that TOP2B deficiency and Hoffman syndrome are manifestations of the same disease with B cell developmental defects. Reason: Confirms the critical role of TOP2B in B cell differentiation. TOP2B deficiency causes a specific block in B cell development while sparing other immune cell lineages. Supporting Evidence: PMID:32128574 Our results indicate that BILU and Hoffman syndromes are manifestations of the same disease, TOP2B deficiency. Importantly, these findings demonstrate a previously unknown critical role of TOP2B in B cell development.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-4641345	ACCEPT	Summary: TAS annotation from Reactome pathway for SUMOylation of TOP2B with SUMO1. TOP2B is SUMOylated in the nucleoplasm as part of the SUMOylation of DNA replication proteins pathway. Reason: Consistent with other evidence for nucleoplasm localization. The Reactome pathway correctly places TOP2B in the nucleoplasm where SUMOylation occurs. Supporting Evidence: Reactome:R-HSA-4641345 TOP2B is SUMOylated with SUMO1 (Mao et al. 2000, Isik et al. 2003). SUMOylation is observed in response to topoisomerase-mediated DNA damage induced by teniposide.
GO:0005634 nucleus	IDA PMID:9155056 The distribution and expression of the two isoforms of DNA t...	ACCEPT	Summary: IDA annotation from immunohistochemistry study of TOP2 isoform distribution in normal and neoplastic tissues. TOP2B localizes to the nucleus and nucleoplasm. Reason: Direct experimental evidence from immunohistochemistry for nuclear localization of TOP2B in human tissues. Supporting Evidence: PMID:9155056 topoisomerase IIbeta has a much more general cell and tissue distribution than has topoisomerase IIalpha.
GO:0005730 nucleolus	IDA PMID:8299728 Discrete localization of different DNA topoisomerases in HeL...	REMOVE	Summary: IDA annotation from subcellular fractionation study suggesting nucleolar localization. However, this conflicts with PMID:9049244 which shows TOP2B is EXCLUDED from nucleoli during interphase. The PMID:9049244 study is more thorough with better controls. Reason: This annotation conflicts with more detailed studies (PMID:9049244) showing TOP2B is excluded from nucleoli during interphase. TOP2B only accumulates in nucleoli under ATP depletion conditions, not during normal interphase. The annotation appears to be incorrect or reflects artifact of the experimental conditions. Supporting Evidence: PMID:9049244 It was most dense in peri-nucleolar regions, but it was clearly always excluded from the interior of the nucleoli (Fig. 4
GO:0005730 nucleolus	IDA PMID:9155056 The distribution and expression of the two isoforms of DNA t...	REMOVE	Summary: IDA annotation for nucleolar localization from PMID:9155056. This conflicts with the detailed study in PMID:9049244 showing TOP2B is excluded from nucleoli. Reason: Conflicts with more detailed immunofluorescence studies in PMID:9049244 showing TOP2B is excluded from nucleoli during normal interphase. Nucleolar accumulation only occurs under ATP depletion conditions. Supporting Evidence: PMID:9049244 In the Hoechst- negative intranucleolar space, immunostaining of topoisomerase IIβ was also negative.
GO:0045870 positive regulation of single stranded viral RNA replication via double stranded DNA intermediate	IMP PMID:16712776 A study of the topoisomerase II activity in HIV-1 replicatio...	KEEP AS NON CORE	Summary: IMP annotation from study of TOP2 activity in HIV-1 replication. TOP2 inhibitors block HIV replication and TOP2B expression increases in infected cells. However, this is a host-pathogen interaction rather than core cellular function. Reason: Valid experimental evidence for TOP2B role in HIV replication, but this represents a host-pathogen interaction exploited by the virus rather than a core cellular function of TOP2B. Supporting Evidence: PMID:16712776 It has been shown that Topoisomerase II activity is required for HIV-1 replication and the enzyme is phosphorylated during early time points of HIV-1 replication.
GO:1990904 ribonucleoprotein complex	ISS GO_REF:0000024	UNDECIDED	Summary: ISS annotation based on sequence similarity to UniProtKB:Q14TE9 (Xenopus TOP2B). The annotation suggests TOP2B is part of an RNP complex. TOP2B does have RNA binding capacity through its C-terminal domain. Reason: The evidence is indirect (sequence similarity). While TOP2B does bind RNA and may associate with RNP complexes, direct evidence for human TOP2B as part of a specific RNP complex is limited. Supporting Evidence: GO_REF:0000024 Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity.
GO:0006265 DNA topological change	IDA PMID:10684600 Mutagenesis of E477 or K505 in the B' domain of human topois...	ACCEPT	Summary: IDA annotation from direct biochemical characterization of human TOP2B. The study examined strand passage activity and magnesium ion requirements. This is strong experimental evidence for DNA topological change function. Reason: Direct biochemical demonstration of DNA topological change activity using purified human TOP2B enzyme. Core function with strong experimental support. Supporting Evidence: PMID:10684600 Mutagenesis of E477 or K505 in the B' domain of human topoisomerase II beta increases the requirement for magnesium ions during strand passage.
GO:0003918 DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) activity	IDA PMID:10684600 Mutagenesis of E477 or K505 in the B' domain of human topois...	ACCEPT	Summary: IDA annotation from direct biochemical characterization. This study directly demonstrated type II topoisomerase activity of human TOP2B using purified enzyme and analyzed catalytic mechanism. Reason: Gold standard experimental evidence for type II topoisomerase activity. Direct biochemical assays with purified human TOP2B enzyme demonstrating strand passage activity. Supporting Evidence: PMID:10684600 A type II topoisomerase is essential for decatenating DNA replication products, and it accomplishes this task by passing one DNA duplex through a transient break in a second duplex.
GO:0005634 nucleus	IDA PMID:17567603 Nuclear interactions of topoisomerase II alpha and beta with...	ACCEPT	Summary: IDA annotation from study of TOP2 interaction with PLSCR1. The study confirmed nuclear localization as part of characterizing the TOP2-PLSCR1 interaction. Reason: Direct experimental evidence for nuclear localization consistent with other studies. Supporting Evidence: PMID:17567603 Nuclear interactions of topoisomerase II alpha and beta with phospholipid scramblase 1.
GO:0005515 protein binding	IPI PMID:10666337 Human topoisomerase IIalpha and IIbeta interact with the C-t...	MODIFY	Summary: IPI annotation showing interaction with p53. Both TOP2A and TOP2B interact with the C-terminal basic region of p53. This is a specific and biologically relevant interaction. Reason: The p53 interaction is specific and biologically important for coupling DNA topology with cell cycle control. Generic protein binding term is uninformative. Proposed replacements: p53 binding Supporting Evidence: PMID:10666337 Human topoisomerase IIalpha and IIbeta interact with the C-terminal region of p53.
GO:0000792 heterochromatin	IDA PMID:9049244 Cell cycle-coupled relocation of types I and II topoisomeras...	ACCEPT	Summary: IDA annotation with colocalizes_with qualifier showing TOP2B colocalizes with heterochromatin. The study showed TOP2B has different distribution from TOP2A, being more associated with heterochromatin regions. Reason: Direct immunofluorescence evidence showing TOP2B colocalization with heterochromatin. This is distinct from the nucleolar localization that is disputed. Supporting Evidence: PMID:9049244 Cell cycle-coupled relocation of types I and II topoisomerases and modulation of catalytic enzyme activities.
GO:0003682 chromatin binding	IDA PMID:9049244 Cell cycle-coupled relocation of types I and II topoisomeras...	ACCEPT	Summary: IDA annotation for chromatin binding from detailed cell cycle study. TOP2B binds to chromatin during interphase but is released during mitosis. Reason: Direct experimental evidence for chromatin binding. TOP2B shows distinct chromatin binding pattern from TOP2A, being associated with heterochromatin and released during mitosis. Genome-scale mapping of catalytically engaged TOP2B (PMID:38377005) further supports chromatin association at active transcription sites. Supporting Evidence: PMID:9049244 Topoisomerase IIbeta is released from the heterochromatin, whereas topoisomerase I and IIalpha remain chromosome bound. PMID:38377005 TOP2Bcc distribution varies with both nucleosome and compartmental chromosome organization. While TOP2Bccs in gene bodies correlate with their level of transcription.
GO:0005634 nucleus	IDA PMID:9049244 Cell cycle-coupled relocation of types I and II topoisomeras...	ACCEPT	Summary: IDA annotation for nuclear localization from detailed cell cycle study of topoisomerase distribution. Reason: Direct immunofluorescence evidence for nuclear localization during interphase. TOP2B is nuclear but released to cytosol during mitosis. Supporting Evidence: PMID:9049244 In mitosis, topoisomerase IIbeta diffused completely into the cytosol, whereas topoisomerases I and IIalpha remained chromosome bound.
GO:0005654 nucleoplasm	IDA PMID:9049244 Cell cycle-coupled relocation of types I and II topoisomeras...	ACCEPT	Summary: IDA annotation for nucleoplasm localization from detailed immunofluorescence study. TOP2B is found throughout the nucleoplasm but excluded from nucleoli. Reason: Direct immunofluorescence evidence. The study clearly shows TOP2B in nucleoplasm, excluded from nucleoli. Supporting Evidence: PMID:9049244 Topoisomerase IIβ exhibited a patchy reticular distribution, markedly different from topoisomerase IIα.
GO:0005730 nucleolus	IDA NOT PMID:9049244 Cell cycle-coupled relocation of types I and II topoisomeras...	ACCEPT	Summary: NOT annotation from PMID:9049244 indicating TOP2B is EXCLUDED from nucleoli during normal interphase. This is important negative evidence that corrects earlier erroneous reports. Reason: Important negative evidence. The detailed immunofluorescence study clearly demonstrates TOP2B exclusion from nucleoli, contradicting earlier reports. TOP2B only accumulates in nucleoli under ATP depletion. Supporting Evidence: PMID:9049244 it was clearly always excluded from the interior of the nucleoli (Fig. 4
GO:0005829 cytosol	IDA PMID:9049244 Cell cycle-coupled relocation of types I and II topoisomeras...	ACCEPT	Summary: IDA annotation for cytosol localization. The study shows TOP2B diffuses into cytosol during mitosis when it is released from chromatin. Reason: Direct experimental evidence. During mitosis, TOP2B is released from chromatin and diffuses into the cytosol. This is distinct from TOP2A which remains chromosome-bound. Supporting Evidence: PMID:9049244 In mitosis, topoisomerase IIbeta diffused completely into the cytosol, whereas topoisomerases I and IIalpha remained chromosome bound.

Gene Description

Existing Annotations Review

Core Functions

Core enzymatic function of TOP2B. Catalyzes ATP-dependent double-strand break formation, strand passage, and religation to resolve DNA topological constraints during transcription and chromatin remodeling.

TOP2B is required for B cell differentiation. Mutations cause complete B cell immunodeficiency (BILU syndrome). Required for transcription of long B cell specification genes including PAX5 and EBF1.

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