TOP3B, short for topoisomerase III beta, is a member of the type IA topoisomerase family. It operates on both DNA and RNA substrates, playing a crucial role in regulating gene expression and maintaining genomic stability [3]. TOP3B is involved in pathways related to resolving R-loops, which are RNA-DNA hybrids that can cause genomic instability if not properly managed [2,4]. Its proper function is essential for normal cell growth and development, and its dysregulation is associated with various diseases.

Analysis in patient and modelled human cells with a disrupted TOP3B gene (similar to a gene knockout model) shows genome instability, an increase in DNA damage, chromosome bridging, and a significant rise in R-loop formation [2]. TOP3B knockout cells also display elevated R-loops, which can be suppressed by TOP3B transfection. Additionally, the absence of TDRD3, which stabilizes TOP3B, leads to an increase in TOP3B cleavage complexes (TOP3Bccs) in DNA and RNA, as well as induced R-loops, γH2AX, and growth defects [1,4].

In conclusion, TOP3B is vital for preventing the accumulation of excessive R-loops and maintaining genome stability. Research on TOP3B, especially through gene-knockout-like models, has revealed its significance in cancer aetiology and neurological diseases such as schizophrenia, autism, and epilepsy [2,3,5,6,7]. Understanding TOP3B's function provides insights into the mechanisms underlying these diseases, potentially guiding future therapeutic strategies.

References:

1. Saha, Sourav, Huang, Shar-Yin Naomi, Yang, Xi, Jenkins, Lisa M, Pommier, Yves. 2023. The TDRD3-USP9X complex and MIB1 regulate TOP3B homeostasis and prevent deleterious TOP3B cleavage complexes. In Nature communications, 14, 7524. doi:10.1038/s41467-023-43151-z. https://pubmed.ncbi.nlm.nih.gov/37980342/

2. Zhang, Tao, Wallis, Mathew, Petrovic, Vida, Kalitsis, Paul, Hudson, Damien F. 2019. Loss of TOP3B leads to increased R-loop formation and genome instability. In Open biology, 9, 190222. doi:10.1098/rsob.190222. https://pubmed.ncbi.nlm.nih.gov/31795919/

3. Moreira, Filipa, Arenas, Miguel, Videira, Arnaldo, Pereira, Filipe. 2021. Molecular Evolution of DNA Topoisomerase III Beta (TOP3B) in Metazoa. In Journal of molecular evolution, 89, 384-395. doi:10.1007/s00239-021-10011-7. https://pubmed.ncbi.nlm.nih.gov/33999213/

4. Saha, Sourav, Yang, Xi, Huang, Shar-Yin Naomi, Wang, Weidong, Pommier, Yves. . Resolution of R-loops by topoisomerase III-β (TOP3B) in coordination with the DEAD-box helicase DDX5. In Cell reports, 40, 111067. doi:10.1016/j.celrep.2022.111067. https://pubmed.ncbi.nlm.nih.gov/35830799/

5. Daghsni, Marwa, Lahbib, Saida, Fradj, Mohamed, Abdelhak, Sonia, M'rad, Ridha. 2018. TOP3B: A Novel Candidate Gene in Juvenile Myoclonic Epilepsy? In Cytogenetic and genome research, 154, 1-5. doi:10.1159/000486945. https://pubmed.ncbi.nlm.nih.gov/29490292/

6. Riley, Jacquelyn D, Delahunty, Carol, Alsadah, Adnan, Mazzola, Sarah, Astbury, Caroline. 2020. Further evidence of GABRA4 and TOP3B as autism susceptibility genes. In European journal of medical genetics, 63, 103876. doi:10.1016/j.ejmg.2020.103876. https://pubmed.ncbi.nlm.nih.gov/32028044/

7. Ranieri, Annaluisa, La Monica, Ilaria, Di Iorio, Maria Rosaria, Lombardo, Barbara, Pastore, Lucio. 2024. Genetic Alterations in a Large Population of Italian Patients Affected by Neurodevelopmental Disorders. In Genes, 15, . doi:10.3390/genes15040427. https://pubmed.ncbi.nlm.nih.gov/38674362/