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Molecular Evolution of DNA Topoisomerase III Beta (TOP3B) in Metazoa

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Abstract

DNA topoisomerase III beta (TOP3B) is unique by operating on both DNA and RNA substrates to regulate gene expression and genomic stability. Mutations in human TOP3B are linked to neurodevelopmental and cognitive disorders, highlighting its relevance for human health. Despite the emerging importance of TOP3B, its precise cellular functions and evolutionary history remain poorly understood. Here, we show that TOP3B is conserved across main metazoan groups and evolved under strong purifying selection. Subdomain IV was identified as the most conserved TOP3B region, in agreement with its role in providing the structural foundation of the protein. On the contrary, subdomain II is the less conserved, possibly because it is the most structurally flexible region of all TOP3B regions. Interestingly, TOP3B residue at position 472, previously associated with schizophrenia, is highly variable across animals, suggesting a more specific role in humans and related species. Finally, we show that all TOP3B CXXC zinc finger motifs previously identified at the protein C-terminal region are retained across metazoans. We also found that the two major methylation sites known to regulate TOP3B activity are located in the most conserved region of the C-terminal arginine-glycine-glycine (RGG) box, suggesting that a similar regulatory mechanism may operate throughout animals. Overall, our results provide a better understanding of the evolution and functional roles of TOP3B.

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Funding

This work was partially supported by a research grant to FM (SFRH/BD/131584/2017) from Fundação para a Ciência e a Tecnologia. MA was supported by a research grant (RYC-2015–18241) from the “Ministerio de Ciencia, Innovación y Universidades” of the Spanish Government.

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Authors and Affiliations

  1. Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), University of Porto, Terminal de Cruzeiros do Porto de Leixões, Avenida General Norton de Matos s/n, 4450-208, Matosinhos, Portugal

    Filipa Moreira

  2. Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua Jorge de Viterbo Ferreira 228, 4450-208, Porto, Portugal

    Filipa Moreira & Arnaldo Videira

  3. Department of Biochemistry, Genetics and Immunology, University of Vigo, 36310, Vigo, Spain

    Miguel Arenas

  4. Centro de Investigaciones Biomédicas (CINBIO), Universidade de Vigo, 36310, Vigo, Spain

    Miguel Arenas

  5. Galicia Sur Health Research Institute (IIS Galicia Sur), 36310, Vigo, Spain

    Miguel Arenas

  6. IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal

    Arnaldo Videira

  7. i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

    Arnaldo Videira

  8. IDENTIFICA Genetic Testing, Rua Simão Bolívar 259 3º Dir Tras, 4470-214, Maia, Portugal

    Filipe Pereira

  9. Department of Life Sciences, Centre for Functional Ecology, University of Coimbra, Calçada Martim de Freitas, 3000-456, Coimbra, Portugal

    Filipe Pereira

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  1. Filipa Moreira
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  2. Miguel Arenas
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  3. Arnaldo Videira
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Correspondence to Filipe Pereira.

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Handling Editor: David Alvarez-Ponce.

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Moreira, F., Arenas, M., Videira, A. et al. Molecular Evolution of DNA Topoisomerase III Beta (TOP3B) in Metazoa. J Mol Evol 89, 384–395 (2021). https://doi.org/10.1007/s00239-021-10011-7

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