In-silico Comparative Analysis of TOP3B Protein Mammals Species with Emphasis on Heterocephalus glaber and Homo sapiens.

Introduction/background: TOP3B (Topoisomerase III-Beta) is a DNA topoisomerase enzyme essential for managing DNA topology during various cellular processes. TOP3B knockout mice typically develop but have a shorter lifespan; however, the exact role of TOP3B is not fully understood. This study aims to investigate the diversity of TOP3B across various mammalian species, with a particular focus on comparing the naked mole-rat (Heterocephalus glaber), known for its exceptional longevity and genomic stability, and humans (Homo sapiens).

Materials and methods: The study analyzed 30 putative TOP3B genes across 23 mammalian species, including Heterocephalus glaber (Hgl), Octodon degus (Ode), Pongo abelii (Pab), Trachypithecus francoisi (Tfr), Cavia porcellus (Cpo), Aotus nancymaae (Ana) and Homo sapiens (Hsa). Further deep in-silico analysis was done by covering structural and functional delivery analysis.

Results: Database searches revealed the presence of two transcript isoforms, X1 and X3, in the naked mole-rat (NMR) and three isoforms in humans (Hsa), while most other species exhibited one to two isoforms. Analyses of conserved domain architecture and de novo motifs indicated noticeable differences in the domain and motif patterns between the NMR and human isoforms. Additionally, multiple sequence alignment identified several mutations at critical sites in the NMR's TOP3B protein, including A46D and G47S, and five other unnamed mutations that may contribute to genomic stability. Evolutionary analyses showed that the TOP3B sequences of the NMR are closely related to those of Cavia porcellus (guinea pig) and Octodon degus (Degus). Furthermore, protein-protein interaction network analyses, along with pathway and molecular docking studies, revealed significant diversity in the interaction patterns of TOP3B between the NMR and humans.

Discussion: The structural diversity and conserved-site mutations in Hgl's TOP3B protein suggest a potential role in promoting genomic stability and extending lifespan. These unique structural features may contribute to the Heterocephalus glaber's exceptional resistance to genomic instability and aging, offering insights into potential longevity mechanisms.

Conclusion: These findings suggest that structure variations and mutations in NMR's TOP3B protein are associated with enhanced genomic stability, which may underlie its remarkable lifespan. This study provides preliminary insights into the potential function of TOP3B in genomic maintenance across species, particularly in aging and longevity.