Base Excision DNA Repair in Disease Susceptibility and Treatment

疾病易感性和治疗中的碱基切除 DNA 修复

• 批准号: 10003714
• 负责人: Vilhelm A Bohr
• 金额: $ 46.28万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10003714
• 关键词: APTX gene; Aging; Animal Model; Back; Base Excision Repairs; Basic Science; Biochemical; Cell Death; Cell Line; Cell Nucleus; Cell Respiration; Cells; Complement component C1; Consumption; DNA; DNA Adducts; DNA Damage; DNA Repair Gene; DNA glycosylase; Data; Defect; Development; Disease; Disease susceptibility; Excision; Foundations; Functional disorder; Genetic Polymorphism; Genome; Goals; Human; Immunologic Deficiency Syndromes; Impairment; Laboratories; Lesion; Ligase; Link; Lipids; Lyase; Maintenance; Malignant Neoplasms; Mitochondria; Modification; Molecular; Nerve Degeneration; Nucleic Acids; Nucleotides; Organism; Oxidation-Reduction; POLB gene; Pathology; Pathway interactions; Poly(ADP-ribose) Polymerases; Polymerase; Predisposition; Process; Proteins; Reactive Oxygen Species; Reporting; Research; Roentgen Rays; Role; Series; Severities; Signal Transduction; Single Strand Break Repair; Site; Structure; System; Uracil; Vertebral column; age related; base; cell growth; cohort; coping; crosslink; cytotoxic; disorder risk; endonuclease; gene repair; genetically modified cells; healthspan; inhibitor/antagonist; mitochondrial dysfunction; neoplastic; nervous system disorder; nuclease; oxidative DNA damage; phosphodiester; repaired; scaffold; seal; stem

Using molecular, biochemical and structural approaches, we have helped define how human BER proteins recognize and coordinately process target lesions. The research has centered on two protein apurinic/apyrimidinic endonuclease 1 (APE1), the major mammalian protein for repairing abasic sites in DNA, and x-ray cross-complementing 1 (XRCC1), a non-enzymatic scaffold that facilitates the efficient execution of single-strand break repair. One of the main basic science goals of the lab is to establish genetically modified cell lines to dissect out the precise contribution of each proposed function of APE1 (i.e. its nuclease activity, redox regulatory role, etc.) in cell growth/viability, genome maintenance, and protection against DNA-damaging agents. Defining which of the many reported functions of APE1 are critical to normal cellular activity is a key step towards understanding the potential relationship of the protein to the aging process and disease risk. With respect to XRCC1, we are investigating its role in mitochondrial dysfunction and how that may contribute to the development or severity of neurological disease. This may stem from the accumulation of DNA damage and an associated activation of poly (ADP-ribose) polymerase 1, (PARP-1), which leads to NAD consumption and impairment of mitochondrial function. XRCC1, unlike many of its interacting partners including TDPI, Aprataxin, PNPK, and POLB, which have been shown to localize to the mitochondria, has been reported to exclusively reside in the nucleus. Thus, we are probing the nucleus-to-mitochondria signaling and examining whether a deficiency in XRCC1 promotes mitochondrial dysfunction that may contribute to disease pathology.

使用分子，生化和结构方法，我们帮助定义了人类BER蛋白如何识别和协调处理靶病变。 这项研究集中在两个蛋白质磷灰蛋白/肾上腺素核酸内切酶1（APE1）上，这是用于修复DNA中的可碱位点的主要哺乳动物蛋白，以及X射线交叉汇编1（XRCC1），一种非酶的caffold，可有效地执行单层损坏修复。实验室的主要基础科学目标之一是建立遗传修饰的细胞系，以剖析APE1的每个提出功能（即其核酸酶活性，氧化还原调节作用等）在细胞生长/生存能力，基因组维持和保护DNA受损剂中的精确贡献。 定义APE1的许多报告的功能中的哪个对正常细胞活性至关重要，这是了解蛋白质与衰老过程和疾病风险的潜在关系的关键步骤。 关于XRCC1，我们正在研究其在线粒体功能障碍中的作用，以及这可能有助于神经系统疾病的发展或严重性。这可能源于DNA损伤的积累以及聚（ADP-核糖）聚合酶1（PARP-1）的相关激活，这导致了线粒体功能的NAD消耗和损害。 XRCC1与许多相互作用的伙伴不同，包括TDPI，Aprataxin，PNPK和POLB，这些伴侣已被证明将其定位于线粒体，据报道仅驻留在细胞核中。因此，我们正在探测细胞核到线粒体信号传导，并检查XRCC1缺乏是否会促进可能导致疾病病理学的线粒体功能障碍。

项目成果

Identification and quantification of DNA repair protein apurinic/apyrimidinic endonuclease 1 (APE1) in human cells by liquid chromatography/isotope-dilution tandem mass spectrometry.

• DOI: 10.1371/journal.pone.0069894
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Kirkali G;Jaruga P;Reddy PT;Tona A;Nelson BC;Li M;Wilson DM 3rd;Dizdaroglu M
• 通讯作者: Dizdaroglu M

Development and evaluation of human AP endonuclease inhibitors in melanoma and glioma cell lines.

• DOI: 10.1038/sj.bjc.6606058
• 发表时间: 2011-02-15
• 期刊: British journal of cancer
• 影响因子: 8.8

Synthetic lethal targeting of DNA double-strand break repair deficient cells by human apurinic/apyrimidinic endonuclease inhibitors.

• DOI: 10.1002/ijc.27512
• 发表时间: 2012-11-15
• 期刊: INTERNATIONAL JOURNAL OF CANCER
• 影响因子: 6.4
• 作者: Sultana, Rebeka;McNeill, Daniel R.;Abbotts, Rachel;Mohammed, Mohammed Z.;Zdzienicka, Malgorzata Z.;Qutob, Haitham;Seedhouse, Claire;Laughton, Charles A.;Fischer, Peter M.;Patel, Poulam M.;Wilson, David M., III;Madhusudan, Srinivasan
• 通讯作者: Madhusudan, Srinivasan

Coordination of DNA single strand break repair.

• DOI: 10.1016/j.freeradbiomed.2016.11.039
• 发表时间: 2017-06
• 期刊: Free radical biology & medicine
• 影响因子: 7.4
• 作者: Abbotts R;Wilson DM 3rd
• 通讯作者: Wilson DM 3rd

Inhibitors of the apurinic/apyrimidinic endonuclease 1 (APE1)/nucleophosmin (NPM1) interaction that display anti-tumor properties.

• DOI: 10.1002/mc.22313
• 发表时间: 2016-05
• 期刊: Molecular carcinogenesis
• 影响因子: 4.6
• 作者: Poletto M;Malfatti MC;Dorjsuren D;Scognamiglio PL;Marasco D;Vascotto C;Jadhav A;Maloney DJ;Wilson DM 3rd;Simeonov A;Tell G
• 通讯作者: Tell G