Mitochondrial DNA Polymerase POLG1 Disease Mutations and Germline Variants Promote Tumorigenic Properties.
Mitochondrial DNA Polymerase POLG1 Disease Mutations and Germline Variants Promote Tumorigenic Properties.
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DOI：
10.1371/journal.pone.0139846
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Singh KK
中科院分区：
文献类型：
--
作者：
Singh B;Owens KM;Bajpai P;Desouki MM;Srinivasasainagendra V;Tiwari HK;Singh KK
线粒体 DNA 聚合酶 γ (POLG1) 的种系突变会诱导线粒体 DNA (mtDNA) 突变、耗竭并降低氧化磷酸化。早些时候，我们鉴定了 POLG1 的体细胞突变以及这些突变在人类癌症中的作用。然而，POLG1 种系变异在人类癌症中的作用尚不清楚。在这项研究中，我们研究了与疾病相关的 POLG1 种系变异、POLG1 基因表达、拷贝数变异和调控在人类癌症中的作用。我们分析了多个癌症数据库中 POLG1 的突变、表达和拷贝数变异，并验证了原发性乳腺肿瘤和乳腺癌细胞系的分析。我们发现 5-aza-2'-脱氧胞苷导致 POLG1、mtDNA 编码基因的表观遗传调控并增加线粒体呼吸。我们对超过 33,000 名欧洲裔美国人和 5,000 名非洲裔美国人的 POLG1 基因进行了全面的基于种族的生物信息学分析。我们发现，一种导致 POLG1 蛋白聚合酶结构域氨基酸 1143 (E1143G) 错义变异的线粒体疾病在欧洲裔美国人（等位基因频率 0.03777）中的患病率是非洲裔美国人（等位基因频率 0.00151）人群的 25 倍。我们发现 POLG1 核酸外切酶和接头区域中的 T251I 和 P587L 错义变异在欧洲裔美国人中也更为普遍。这些变体的表达增加了葡萄糖的消耗，减少了 ATP 的产生并增加了基质胶的侵袭。有趣的是，这些变体的条件表达表明，这些种系变体赋予的基质胶侵袭特性是可逆的，表明表观遗传调节剂的作用。事实上，我们鉴定了一组 miRNA，其表达在变异表达关闭后是可逆的。总之，我们的研究证明了 POLG1 在人类癌症中遗传和表观遗传调控的改变，并表明 POLG1 种系变异在促进致瘤特性中的作用。
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.