TOP2B

What is TOP2B?

The TOP2B protein is an enzyme encoded by the TOP2B gene, discovered as part of vast research activities aimed at identifying and understanding the diverse ensemble of human proteins and genes. As a part of the topoisomerase family of proteins, the TOP2B protein is classified as a type II topoisomerase, playing a fundamental role in essential cellular mechanics such as transcription, replication, and chromosomal segregation.

Gene Locus and Protein Structure

The gene locus of TOP2B is positioned at 3p24.1, the short (p) arm of chromosome 3 at position 24.1. Structurally, the TOP2B protein is a large, well-conserved molecule with a molecular mass of 182 kDa. It contains several functional domains, including an ATPase domain, a DNA-binding core, and a C-terminal domain involved in protein-protein interactions. The protein functions as a homodimer and has a unique ability to change DNA topology by generating a transient double-strand break, through which it passes an intact DNA helix.

Function of TOP2B Protein

Preeminent in its utility, TOP2B protein ensures the correct winding and unwinding of DNA, which is crucial during various phases of the cellular life cycle like DNA replication, transcription, recombination, and chromosomal segregation. It acts by creating transient double-strand breaks in supercoiled DNA, maintaining the topological state of DNA in the nucleus. The ability of TOP2B to untangle supercoiled DNA strands supports the prevention of detrimental tangles and knots during critical cellular processes.

TOP2B Protein-Related Signal Pathway

With respect to signal transduction, the involvement of TOP2B protein is a key factor in DNA damage response (DDR) pathways. Upon detecting DNA damage, these pathways trigger cellular responses, such as DNA repair, cell cycle arrest, or apoptosis. Notably, TOP2B works in synergy with PARP1, a protein involved in DNA repair, to signal DNA damage and enable repair mechanisms.

TOP2B Protein-Associated Diseases

Mutations in TOP2B protein or its pathway dysfunctions have been associated with diverse pathological conditions. Its interaction with other proteins implicated in genetic disorders, such as ataxia-telangiectasia and Rothmund-Thomson syndrome, affirms its importance in maintaining genome integrity. Recently, research has linked TOP2B to neurodegenerative diseases, particularly Parkinson's disease, and some forms of epilepsy, indicating a key role in maintaining normal neuronal function. Moreover, its involvement in cell replication and growth makes it a target for cancer therapeutics.

TOP2B Protein's Utility in Biomedical Applications

TOP2B protein has substantial implications in biomedical research, most notably in cancer therapeutics. As TOP2B is critical for cell replication, inhibitors targeting this protein are effective in hindering the proliferation of cancer cells. Notably, Etoposide, a chemotherapeutic agent, targets TOP2B, causing DNA damage and subsequent cell death, thereby preventing tumor growth.

Recently, research efforts have turned towards understanding the role of TOP2B protein in neurodegenerative diseases, offering new avenues for targeted therapeutic approaches in neurological disorders. Thus, understanding the intricate workings of the TOP2B protein could manifest in the form of innovative biomedical applications, reinforcing the necessity to explore complex genetic mechanisms thoroughly.

The recombinant TOP2B protein has numerous applications in the biomedical field. They are utilized in biochemical assays to decipher the pathway and mechanisms involving DNA topology and gene expression regulation. They are particularly useful in understanding the mechanism of action of various cancer drugs that target topoisomerase enzymes.

Furthermore, in drug discovery and development, recombinant TOP2B protein is essential in screening new potential drugs targeting the TOP2B protein to obtain potential candidates for further validation and development. For instance, drugs that inhibit TOP2B protein are considered potential anticancer agents.

The TOP2B protein, though complex in structure and function, presents an invaluable asset in the realm of genetics and biomedicine. Despite advancements, our understanding of this protein's intricate mechanisms, related signaling pathways, disease implications and potential therapeutic uses is still evolving. As we delve deeper into the labyrinth of genetic complexities, TOP2B protein stands as an assertive reminder of the vital knowledge that every gene and protein imparts - a knowledge that holds the power to transform how we understand and treat diseases.

Case1: Gonzalez-Buendia E, et al. Clin Cancer Res. 2021.
Topoisomerase IIB (TOP2B), an enzyme that decoils and releases torsional forces in DNA, is overexpressed in a subset of gliomas. Therefore, the researchers investigated its role in epigenetic regulation in these tumors.

To investigate the role of TOP2B in epigenetic regulation in gliomas, they performed paired chromatin immunoprecipitation sequencing for TOP2B and RNA-sequencing analysis of glioma cell lines with and without TOP2B inhibition and in human glioma specimens.

The study discovered that TOP2B modulates transcription of multiple oncogenes in human gliomas. TOP2B regulated transcription only at sites where it was enzymatically active, but not at all native binding sites. In particular, TOP2B activity localized in enhancers, promoters, and introns of PDGFRA and MYC, facilitating their expression.

Fig1. TOP2B expression determined by RNA-seq and Western blot on human glioma cell lines (two independent experiments on TS543, BT142, 0777A, SNB19) and human glioma specimens (NU01482, NU01722; left). Genome-wide distribution of TOP2B native binding and activity peaks determined by DMSO and etoposide (Et) ChIP-seq in different glioma cell lines were performed (top-center panel; TS543 two DMSO/etoposide experimental replicates, BT142 two DMSO/etoposide experimental replicates, 0777A 1 DMSO/etoposide experiment, SNB19 2 DMSO/etoposide experiments) and human glioma tumors (bottom-center panel; NU01482 1 DMSO/etoposide experimental replicate, NU01722 1 DMSO/etoposide experimental replicate).

Case2: Pan M, et al. Nat Commun. 2021.
Existing clinically approved chemotherapeutics have well-documented off-target interactions with TOP2B, which have previously been shown to cause both therapy-induced leukemia and cardiotoxicity-often-fatal adverse events, which can emerge several years after treatment. Thus, while researchers show that combination therapies involving CX-5461 have promising anti-tumor activity in vivo in neuroblastoma, their identification of TOP2B as the primary target of CX-5461 indicates unexpected safety concerns that should be examined in ongoing phase II clinical trials in adult patients before pursuing clinical studies in children.

Fig1. CX-5461 primarily targets the TOP2B paralog.

c Spearman correlations of the expression of all genes with CX-5461 sensitivity in GDSC neuroblastoma cell lines, with TOP2A and TOP2B highlighted. P-values are from two-sided Pearson's correlation tests. d Spearman correlation of TOP2B expression with sensitivity (1/IC50) of all drugs screened in GDSC neuroblastoma cell lines. CX-5461, etoposide, and doxorubicin are highlighted. P-values are from two-sided Pearson's correlation tests. n CX-5461-Diazirine structure (left) and quantification of TOP2B protein signal detected in CX-5461-Diazirine treated cells after streptavidin purification (right).

Case3: Khazeem MM, et al. Mol Neurobiol. 2022.
Using a combination of pharmacological inhibition and targeted gene inactivation, the researchers have probed the requirement for DNA topoisomerase IIB (TOP2B) in RA-induced gene expression and differentiation and in the balance between adrenergic neuronal versus mesenchymal transcription programmes. They found that expression of many, but not all genes that are rapidly induced by ATRA in SH-SY5Y cells was significantly reduced in the TOP2B null cells. The study concluded that TOP2B is required to fully maintain the adrenergic neural-like transcriptional signature of SH-SY5Y cells and to suppress the alternative mesenchymal epithelial-like epigenetic state.

Fig1. Plot illustrating the relationship between the presence of TOP2B binding peaks and gene expression changes between WT and BKO cells. Genes are categorised according to the evidence for TOP2B binding from inspection of a published glioma ChIP-seq data set [62] according to the following scheme: none, no peaks observed in the promoter region or gene body; multiple, multiple peaks present; promoter, peak or peaks present in the promoter region; internal with CTCF, TOP2B peak or peaks at a gene-internal position coincident with CTCF binding; and internal, peak or peaks within the gene, not associated with CTCF.

TOP2B has several biochemical functions, for example, ATP binding,DNA binding, bending,DNA topoisomerase type II (ATP-hydrolyzing) activity. Some of the functions are cooperated with other proteins, some of the functions could acted by TOP2B itself. We selected most functions TOP2B had, and list some proteins which have the same functions with TOP2B. You can find most of the proteins on our site.

TOP2B has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with TOP2B here. Most of them are supplied by our site. Hope this information will be useful for your research of TOP2B.

USF1;ESR1;Top2b;fas_human_gene;PRKCD;UVRAG