Distribution bias and biochemical characterization of TOP1MT single nucleotide variants

Abstract 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 rs22...

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Autores principales:	Hongliang Zhang, Yeonee Seol, Keli Agama, Keir C. Neuman, Yves Pommier
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ab9c848683b442378bbba0097b3e7468
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spelling	oai:doaj.org-article:ab9c848683b442378bbba0097b3e74682021-12-02T16:06:49ZDistribution bias and biochemical characterization of TOP1MT single nucleotide variants10.1038/s41598-017-09258-22045-2322https://doaj.org/article/ab9c848683b442378bbba0097b3e74682017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-09258-2https://doaj.org/toc/2045-2322Abstract 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.Hongliang ZhangYeonee SeolKeli AgamaKeir C. NeumanYves PommierNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hongliang Zhang Yeonee Seol Keli Agama Keir C. Neuman Yves Pommier Distribution bias and biochemical characterization of TOP1MT single nucleotide variants
description	Abstract 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.
format	article
author	Hongliang Zhang Yeonee Seol Keli Agama Keir C. Neuman Yves Pommier
author_facet	Hongliang Zhang Yeonee Seol Keli Agama Keir C. Neuman Yves Pommier
author_sort	Hongliang Zhang
title	Distribution bias and biochemical characterization of TOP1MT single nucleotide variants
title_short	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_sort	distribution bias and biochemical characterization of top1mt single nucleotide variants
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/ab9c848683b442378bbba0097b3e7468
work_keys_str_mv	AT hongliangzhang distributionbiasandbiochemicalcharacterizationoftop1mtsinglenucleotidevariants AT yeoneeseol distributionbiasandbiochemicalcharacterizationoftop1mtsinglenucleotidevariants AT keliagama distributionbiasandbiochemicalcharacterizationoftop1mtsinglenucleotidevariants AT keircneuman distributionbiasandbiochemicalcharacterizationoftop1mtsinglenucleotidevariants AT yvespommier distributionbiasandbiochemicalcharacterizationoftop1mtsinglenucleotidevariants
_version_	1718384862876925952

Distribution bias and biochemical characterization of TOP1MT single nucleotide variants

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