title: Mitochondrial DNA Polymerase POLG1 Disease Mutations and Germline Variants Promote Tumorigenic Properties.
abstract: Germline mutations in mitochondrial DNA polymerase gamma (POLG1) induce mitochondrial DNA (mtDNA) mutations, depletion, and decrease oxidative phosphorylation. Earlier, we identified somatic mutations in POLG1 and the contribution of these mutations in human cancer. However, a role for germline variations in POLG1 in human cancers is unknown. In this study, we examined a role for disease associated germline variants of POLG1, POLG1 gene expression, copy number variation and regulation in human cancers. We analyzed the mutations, expression and copy number variation in POLG1 in several cancer databases and validated the analyses in primary breast tumors and breast cancer cell lines. We discovered 5-aza-2'-deoxycytidine led epigenetic regulation of POLG1, mtDNA-encoded genes and increased mitochondrial respiration. We conducted comprehensive race based bioinformatics analyses of POLG1 gene in more than 33,000 European-Americans and 5,000 African-Americans. We identified a mitochondrial disease causing missense variation in polymerase domain of POLG1 protein at amino acid 1143 (E1143G) to be 25 times more prevalent in European-Americans (allele frequency 0.03777) when compared to African-American (allele frequency 0.00151) population. We identified T251I and P587L missense variations in exonuclease and linker region of POLG1 also to be more prevalent in European-Americans. Expression of these variants increased glucose consumption, decreased ATP production and increased matrigel invasion. Interestingly, conditional expression of these variants revealed that matrigel invasion properties conferred by these germline variants were reversible suggesting a role of epigenetic regulators. Indeed, we identified a set of miRNA whose expression was reversible after variant expression was turned off. Together, our studies demonstrate altered genetic and epigenetic regulation of POLG1 in human cancers and suggest a role for POLG1 germline variants in promoting tumorigenic properties.
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, United States of America.
authors.forename: Bhupendra
authors.initials: B
authors.lastname: Singh
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, United States of America.
authors.forename: Kjerstin M
authors.initials: KM
authors.lastname: Owens
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, United States of America.
authors.forename: Prachi
authors.initials: P
authors.lastname: Bajpai
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN, United States of America.
authors.forename: Mohamed Mokhtar
authors.initials: MM
authors.lastname: Desouki
authors.affiliation: Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, United States of America.
authors.forename: Vinodh
authors.initials: V
authors.lastname: Srinivasasainagendra
authors.affiliation: Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, United States of America.
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Tiwari
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, United States of America; Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Department of Environmental Health, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Center for Aging, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; UAB Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Birmingham Veterans Affairs Medical Center, Birmingham, AL, 35294, United States of America.
authors.forename: Keshav K
authors.initials: KK
authors.lastname: Singh
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D056915:DNA Copy Number Variations; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D018095:Germ-Line Mutation; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000150:complications* / Q000235:genetics*; D009154:Mutation; D009369:Neoplasms / Q000209:etiology*
chemical_list: D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human