DNA Lesion Bypass in Sulfolobus solfataricus
硫磺硫化叶菌 DNA 损伤旁路
基本信息
- 批准号:1856617
- 负责人:
- 金额:$ 67.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:Continuing Grant
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-06-16 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
DNA is the genetic material that gives each cell and organism its unique character. The accurate duplication of DNA as well as its subsequent transfer from parent to offspring is critical for life. Some environmental factors such as chemical carcinogens, UV light, or even natural cellular processes can cause oxidative or physical damage to our DNA, which can cause mutations or temporarily block its duplication. In fact, it has been estimated that there are tens of thousands of damaged DNA sites (lesions) in each human cell per day. Lesions in genomic DNA of other organisms are also widespread. If left unrepaired, these lesions can inhibit the duplication of DNA, cause cell death, or detrimental mutations. This project will use cutting-edge biophysical techniques to investigate how a commonly occurring oxidative DNA lesion prevents proteins from accurately duplicating the DNA. The results generated from this project will determine the consequences of DNA damage at the molecular level. In addition to its scientific importance, the project will also support undergraduate and graduate students at The Ohio State University with opportunities to receive scientific training, provide them tools for designing and testing scientific hypotheses, as well as learning about the nature of scientific discovery. Cellular DNA is frequently damaged by both endogenous and exogenous sources to form a myriad of DNA damaged sites, which can stall the cellular DNA replication machinery during genome duplication. Some key proteins for DNA replication are the replicative DNA polymerases, which synthesize the majority of DNA, and translesion synthesis (TLS) DNA polymerases, which bypass and extend DNA across from damaged DNA sites but often in an error-prone way. The processivity factor PCNA enhances the ability of replicative polymerases to synthesize long stretches of DNA and plays a key role in polymerase switching at sites of DNA damage. It is not known how common DNA lesions affect the conformational dynamics of replicative and TLS polymerases in solution. Furthermore, it is not known how these two different types of polymerases are switched at a lesion site. To study the first mechanistic question, the project will utilize Förster resonance energy transfer techniques and a stopped-flow apparatus, a rapid mixer, to monitor the conformational dynamics of a replicative polymerase and a TLS polymerase during binding to substrates, or PCNA, as well as catalysis. To elucidate molecular details of polymerase switching, this project will employ cutting-edge single molecule techniques to investigate how a replicative polymerase and a TLS polymerase are switched on and off at a DNA damaged site with the help of PCNA. The project will also offer undergraduate and graduate students at The Ohio State University opportunities to receive important scientific training in the field of advanced enzymology. The project will provide them training in designing and testing scientific hypotheses as well as support for further career development and educational opportunities in STEM fields.
DNA是赋予每个细胞和生物体独特特征的遗传物质。DNA的准确复制以及随后从父母到后代的转移对生命至关重要。一些环境因素,如化学致癌物,紫外线,甚至自然细胞过程,都可能对我们的DNA造成氧化或物理损伤,从而导致突变或暂时阻止其复制。事实上,据估计,每天每个人类细胞中有数万个受损的DNA位点(病变)。其他生物体基因组DNA的损伤也很普遍。如果不修复,这些病变可能会抑制DNA的复制,导致细胞死亡或有害的突变。该项目将使用尖端的生物物理技术来研究常见的氧化DNA损伤如何阻止蛋白质准确复制DNA。该项目产生的结果将在分子水平上确定DNA损伤的后果。除了其科学的重要性,该项目还将支持本科生和研究生在俄亥俄州州立大学有机会接受科学培训,为他们提供设计和测试科学假设的工具,以及了解科学发现的性质。 细胞DNA经常受到内源性和外源性来源的损伤,形成无数的DNA损伤位点,这可以在基因组复制期间停止细胞DNA复制机制。DNA复制的一些关键蛋白质是复制性DNA聚合酶,其合成大部分DNA,以及跨损伤合成(TLS)DNA聚合酶,其绕过并延伸DNA穿过受损的DNA位点,但通常以易于出错的方式。持续合成因子PCNA增强复制型聚合酶合成长链DNA的能力,并在DNA损伤位点的聚合酶转换中起关键作用。目前尚不清楚常见的DNA损伤如何影响溶液中复制型和TLS聚合酶的构象动力学。此外,还不知道这两种不同类型的聚合酶如何在病变部位转换。为了研究第一个机制问题,该项目将利用Förster共振能量转移技术和停流装置,快速混合器,来监测复制聚合酶和TLS聚合酶在与底物或PCNA结合以及催化过程中的构象动力学。为了阐明聚合酶转换的分子细节,该项目将采用尖端的单分子技术来研究复制聚合酶和TLS聚合酶如何在PCNA的帮助下在DNA损伤位点打开和关闭。该项目还将为俄亥俄州州立大学的本科生和研究生提供在高级酶学领域接受重要科学培训的机会。该项目将为他们提供设计和测试科学假设的培训,并为STEM领域的进一步职业发展和教育机会提供支持。
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Elucidating molecular interactions of L-nucleotides with HIV-1 reverse transcriptase and mechanism of M184V-caused drug resistance
- DOI:10.1038/s42003-019-0706-x
- 发表时间:2019-12-13
- 期刊:
- 影响因子:5.9
- 作者:Hung, Magdeleine;Tokarsky, E. John;Lansdon, Eric B.
- 通讯作者:Lansdon, Eric B.
Kinetic Investigation of Translesion Synthesis across a 3-Nitrobenzanthrone-Derived DNA Lesion Catalyzed by Human DNA Polymerase Kappa
人类 DNA 聚合酶 Kappa 催化的 3-硝基苯并蒽酮衍生 DNA 损伤跨损伤合成的动力学研究
- DOI:10.1021/acs.chemrestox.9b00219
- 发表时间:2019
- 期刊:
- 影响因子:4.1
- 作者:Phi, Kenneth K.;Smith, Madison C.;Tokarsky, E. John;Suo, Zucai
- 通讯作者:Suo, Zucai
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Zucai Suo其他文献
Kinetic Investigation of Resistance to Islatravir Conferred by Mutations in HIV-1 Reverse Transcriptase
HIV - 1逆转录酶突变赋予对艾斯拉韦耐药的动力学研究
- DOI:
10.1016/j.jmb.2025.169100 - 发表时间:
2025-06-15 - 期刊:
- 影响因子:4.500
- 作者:
Nikita Zalenski;Brianna R. Meredith;Derek J. Savoie;Mohamed J. Naas;David J. Suo;Daniel Betancourt;Turner W. Seay;Zucai Suo - 通讯作者:
Zucai Suo
Zucai Suo的其他文献
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{{ truncateString('Zucai Suo', 18)}}的其他基金
DNA Lesion Bypass in Sulfolobus solfataricus
硫磺硫化叶菌 DNA 损伤旁路
- 批准号:
1716168 - 财政年份:2017
- 资助金额:
$ 67.96万 - 项目类别:
Continuing Grant
Mechanistic Investigation of DNA Lesion Bypass
DNA 损伤旁路的机制研究
- 批准号:
0960961 - 财政年份:2010
- 资助金额:
$ 67.96万 - 项目类别:
Continuing Grant
CAREER: Kinetic, Dynamic, and Structure-Function Relationship Studies of a Y-family Polymerase
职业:Y 家族聚合酶的动力学、动态和结构功能关系研究
- 批准号:
0447899 - 财政年份:2005
- 资助金额:
$ 67.96万 - 项目类别:
Continuing Grant
相似海外基金
DNA Lesion Bypass in Sulfolobus solfataricus
硫磺硫化叶菌 DNA 损伤旁路
- 批准号:
1716168 - 财政年份:2017
- 资助金额:
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Environmental DNA Lesions and Mutagenesis: Molecular Mechanisms of Lesion Recognition for Repair and Polymerase Bypass
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10460604 - 财政年份:2016
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10612958 - 财政年份:2016
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$ 67.96万 - 项目类别:
Environmental DNA Lesions and Mutagenesis: Molecular Mechanisms of Lesion Recognition for Repair and Polymerase Bypass
环境 DNA 损伤和诱变:损伤识别修复和聚合酶旁路的分子机制
- 批准号:
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Unveiling the mechanism for Spartan-mediated DNA lesion bypass and the implications for breast cancer treatment
揭示 Spartan 介导的 DNA 损伤旁路机制及其对乳腺癌治疗的影响
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8982870 - 财政年份:2015
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黏连蛋白在 DNA 损伤人类细胞病变旁路中的作用
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9025476 - 财政年份:2014
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黏连蛋白在 DNA 损伤人类细胞病变旁路中的作用
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STRUCT STUD DNA-LESION BYPASS AND EUKARYOTIC TRANSLATIONAL REGULATION
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