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Distribution bias and biochemical characterization of TOP1MT single nucleotide variants

Mitochondrial topoisomerase I (TOP1MT) is a type IB topoisomerase encoded in the nucleus of vertebrate cells. In contrast to the other five human topoisomerases, TOP1MT possesses two high frequency single nucleotide variants (SNVs), rs11544484 (V256I, Minor Allele Frequency = 0.27) and rs2293925 (R5...

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Autores principales: Zhang, Hongliang, Seol, Yeonee, Agama, Keli, Neuman, Keir C., Pommier, Yves
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5561071/
https://www.ncbi.nlm.nih.gov/pubmed/28819183
http://dx.doi.org/10.1038/s41598-017-09258-2
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author Zhang, Hongliang
Seol, Yeonee
Agama, Keli
Neuman, Keir C.
Pommier, Yves
author_facet Zhang, Hongliang
Seol, Yeonee
Agama, Keli
Neuman, Keir C.
Pommier, Yves
author_sort Zhang, Hongliang
collection PubMed
description Mitochondrial topoisomerase I (TOP1MT) is a type IB topoisomerase encoded in the nucleus of vertebrate cells. In contrast to the other five human topoisomerases, TOP1MT possesses two high frequency single nucleotide variants (SNVs), rs11544484 (V256I, Minor Allele Frequency = 0.27) and rs2293925 (R525W, MAF = 0.45), which tend to be mutually exclusive across different human ethnic groups and even more clearly in a cohort of 129 US patients with breast cancer and in the NCI-60 cancer cell lines. We expressed these two TOP1MT variants and the double-variant (V256I-R525W) as recombinant proteins, as well as a less common variant E168G (rs200673353, MAF = 0.001), and studied their biochemical properties by magnetic tweezers-based supercoil relaxation and classical DNA relaxation assays. Variants showed reduced DNA relaxation activities, especially the V256I variant towards positively supercoiled DNA. We also found that the V256I variant was enriched to MAF = 0.64 in NCI-60 lung carcinoma cell lines, whereas the TOP1MT R525W was enriched to MAF = 0.65 in the NCI-60 melanoma cell lines. Moreover, TOP1MT expression correlated with the 256 variants in the NCI-60 lung carcinoma cell lines, valine with high expression and isoleucine with low expression. Our results are discussed in the context of evolution between the nuclear and mitochondrial topoisomerases and potential cancer predisposition.
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spelling pubmed-55610712017-08-18 Distribution bias and biochemical characterization of TOP1MT single nucleotide variants Zhang, Hongliang Seol, Yeonee Agama, Keli Neuman, Keir C. Pommier, Yves Sci Rep Article Mitochondrial topoisomerase I (TOP1MT) is a type IB topoisomerase encoded in the nucleus of vertebrate cells. In contrast to the other five human topoisomerases, TOP1MT possesses two high frequency single nucleotide variants (SNVs), rs11544484 (V256I, Minor Allele Frequency = 0.27) and rs2293925 (R525W, MAF = 0.45), which tend to be mutually exclusive across different human ethnic groups and even more clearly in a cohort of 129 US patients with breast cancer and in the NCI-60 cancer cell lines. We expressed these two TOP1MT variants and the double-variant (V256I-R525W) as recombinant proteins, as well as a less common variant E168G (rs200673353, MAF = 0.001), and studied their biochemical properties by magnetic tweezers-based supercoil relaxation and classical DNA relaxation assays. Variants showed reduced DNA relaxation activities, especially the V256I variant towards positively supercoiled DNA. We also found that the V256I variant was enriched to MAF = 0.64 in NCI-60 lung carcinoma cell lines, whereas the TOP1MT R525W was enriched to MAF = 0.65 in the NCI-60 melanoma cell lines. Moreover, TOP1MT expression correlated with the 256 variants in the NCI-60 lung carcinoma cell lines, valine with high expression and isoleucine with low expression. Our results are discussed in the context of evolution between the nuclear and mitochondrial topoisomerases and potential cancer predisposition. Nature Publishing Group UK 2017-08-17 /pmc/articles/PMC5561071/ /pubmed/28819183 http://dx.doi.org/10.1038/s41598-017-09258-2 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Zhang, Hongliang
Seol, Yeonee
Agama, Keli
Neuman, Keir C.
Pommier, Yves
Distribution bias and biochemical characterization of TOP1MT single nucleotide variants
title Distribution bias and biochemical characterization of TOP1MT single nucleotide variants
title_full Distribution bias and biochemical characterization of TOP1MT single nucleotide variants
title_fullStr Distribution bias and biochemical characterization of TOP1MT single nucleotide variants
title_full_unstemmed Distribution bias and biochemical characterization of TOP1MT single nucleotide variants
title_short Distribution bias and biochemical characterization of TOP1MT single nucleotide variants
title_sort distribution bias and biochemical characterization of top1mt single nucleotide variants
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5561071/
https://www.ncbi.nlm.nih.gov/pubmed/28819183
http://dx.doi.org/10.1038/s41598-017-09258-2
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