AI Article Synopsis
- - Mitochondrial topoisomerase I (TOP1MT) is a unique type IB topoisomerase primarily encoded in the nucleus and has two common single nucleotide variants (SNVs) that vary across different ethnic groups and are associated with breast cancer.
- - Experiments with recombinant proteins showed these variants, especially V256I, had reduced DNA relaxation activity, particularly towards positively supercoiled DNA, highlighting their biochemical differences.
- - Notably, the V256I variant was more common in lung carcinoma cell lines, while the R525W variant was more prevalent in melanoma cell lines, suggesting a link between these variants and specific cancer types, along with implications for the evolution of topoisomerases and cancer
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5561071 | PMC |
| http://dx.doi.org/10.1038/s41598-017-09258-2 | DOI Listing |
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