Corey Thomas, Lisbeth Avalos-Irving, Jorge Victorino, Sydney Green, Morgan Andrews, Naisha Rodrigues, Sarah Ebirim, Ayden Mudd and Jamie B. Towle-Weicksel*,
{"title":"黑色素瘤衍生的 DNA 聚合酶 Theta 变体显示出改变的 DNA 聚合酶活性","authors":"Corey Thomas, Lisbeth Avalos-Irving, Jorge Victorino, Sydney Green, Morgan Andrews, Naisha Rodrigues, Sarah Ebirim, Ayden Mudd and Jamie B. Towle-Weicksel*, ","doi":"10.1021/acs.biochem.3c00670","DOIUrl":null,"url":null,"abstract":"<p >DNA polymerase θ (Pol θ or POLQ) is primarily involved in repairing double-stranded breaks in DNA through an alternative pathway known as microhomology-mediated end joining (MMEJ) or theta-mediated end joining (TMEJ). Unlike other DNA repair polymerases, Pol θ is thought to be highly error-prone yet critical for cell survival. We have identified several POLQ gene variants from human melanoma tumors that experience altered DNA polymerase activity, including a propensity for incorrect nucleotide selection and reduced polymerization rates compared to WT Pol θ. Variants are 30-fold less efficient at incorporating a nucleotide during repair and up to 70-fold less accurate at selecting the correct nucleotide opposite a templating base. This suggests that aberrant Pol θ has reduced DNA repair capabilities and may also contribute to increased mutagenesis. Moreover, the variants were identified in established tumors, suggesting that cancer cells may use mutated polymerases to promote metastasis and drug resistance.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":null,"pages":null},"PeriodicalIF":2.9000,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.biochem.3c00670","citationCount":"0","resultStr":"{\"title\":\"Melanoma-Derived DNA Polymerase Theta Variants Exhibit Altered DNA Polymerase Activity\",\"authors\":\"Corey Thomas, Lisbeth Avalos-Irving, Jorge Victorino, Sydney Green, Morgan Andrews, Naisha Rodrigues, Sarah Ebirim, Ayden Mudd and Jamie B. Towle-Weicksel*, \",\"doi\":\"10.1021/acs.biochem.3c00670\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >DNA polymerase θ (Pol θ or POLQ) is primarily involved in repairing double-stranded breaks in DNA through an alternative pathway known as microhomology-mediated end joining (MMEJ) or theta-mediated end joining (TMEJ). Unlike other DNA repair polymerases, Pol θ is thought to be highly error-prone yet critical for cell survival. We have identified several POLQ gene variants from human melanoma tumors that experience altered DNA polymerase activity, including a propensity for incorrect nucleotide selection and reduced polymerization rates compared to WT Pol θ. Variants are 30-fold less efficient at incorporating a nucleotide during repair and up to 70-fold less accurate at selecting the correct nucleotide opposite a templating base. This suggests that aberrant Pol θ has reduced DNA repair capabilities and may also contribute to increased mutagenesis. Moreover, the variants were identified in established tumors, suggesting that cancer cells may use mutated polymerases to promote metastasis and drug resistance.</p>\",\"PeriodicalId\":28,\"journal\":{\"name\":\"Biochemistry Biochemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.9000,\"publicationDate\":\"2024-04-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://pubs.acs.org/doi/epdf/10.1021/acs.biochem.3c00670\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biochemistry Biochemistry\",\"FirstCategoryId\":\"1\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acs.biochem.3c00670\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochemistry Biochemistry","FirstCategoryId":"1","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.biochem.3c00670","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
DNA 聚合酶θ(Pol θ 或 POLQ)主要通过一种被称为微同源物介导的末端连接(MMEJ)或θ介导的末端连接(TMEJ)的替代途径参与 DNA 双链断裂的修复。与其他 DNA 修复聚合酶不同,Pol θ 被认为极易出错,但对细胞存活至关重要。我们从人类黑色素瘤肿瘤中发现了几种 POLQ 基因变异体,它们的 DNA 聚合酶活性发生了改变,包括核苷酸选择错误的倾向以及与 WT Pol θ 相比聚合率降低。变异体在修复过程中整合核苷酸的效率要低 30 倍,选择与模板碱基相对的正确核苷酸的准确性也要低 70 倍。这表明,畸变 Pol θ 的 DNA 修复能力降低,也可能导致突变增加。此外,这些变体是在已确诊的肿瘤中发现的,这表明癌细胞可能利用突变的聚合酶来促进转移和耐药性。
Melanoma-Derived DNA Polymerase Theta Variants Exhibit Altered DNA Polymerase Activity
DNA polymerase θ (Pol θ or POLQ) is primarily involved in repairing double-stranded breaks in DNA through an alternative pathway known as microhomology-mediated end joining (MMEJ) or theta-mediated end joining (TMEJ). Unlike other DNA repair polymerases, Pol θ is thought to be highly error-prone yet critical for cell survival. We have identified several POLQ gene variants from human melanoma tumors that experience altered DNA polymerase activity, including a propensity for incorrect nucleotide selection and reduced polymerization rates compared to WT Pol θ. Variants are 30-fold less efficient at incorporating a nucleotide during repair and up to 70-fold less accurate at selecting the correct nucleotide opposite a templating base. This suggests that aberrant Pol θ has reduced DNA repair capabilities and may also contribute to increased mutagenesis. Moreover, the variants were identified in established tumors, suggesting that cancer cells may use mutated polymerases to promote metastasis and drug resistance.
期刊介绍:
Biochemistry provides an international forum for publishing exceptional, rigorous, high-impact research across all of biological chemistry. This broad scope includes studies on the chemical, physical, mechanistic, and/or structural basis of biological or cell function, and encompasses the fields of chemical biology, synthetic biology, disease biology, cell biology, nucleic acid biology, neuroscience, structural biology, and biophysics. In addition to traditional Research Articles, Biochemistry also publishes Communications, Viewpoints, and Perspectives, as well as From the Bench articles that report new methods of particular interest to the biological chemistry community.