Base Excision DNA Repair in Disease Susceptibility and Treatment

使用分子，生物化学和结构的方法，我们已经帮助确定人类BER蛋白如何识别和协调处理靶病变。 该研究集中在两种蛋白质脱嘌呤/脱嘧啶核酸内切酶1（APE 1），这是修复DNA中脱碱基位点的主要哺乳动物蛋白质，以及X射线交叉互补1（XRCC 1），这是一种促进有效执行单链断裂修复的非酶支架。该实验室的主要基础科学目标之一是建立转基因细胞系，以剖析APE 1的每种拟议功能（即其核酸酶活性，氧化还原调节作用等）的精确贡献。在细胞生长/活力、基因组维持和对DNA损伤剂的保护方面。 确定APE 1的许多报道功能中哪些对正常细胞活性至关重要，是了解蛋白质与衰老过程和疾病风险的潜在关系的关键一步。 关于XRCC 1，我们正在研究它在线粒体功能障碍中的作用，以及它如何导致神经系统疾病的发展或严重程度。这可能源于DNA损伤的积累和相关的聚（ADP-核糖）聚合酶1（PARP-1）的活化，其导致NAD消耗和线粒体功能的损害。 XRCC 1与其许多相互作用的伙伴（包括TDPI、Aprataxin、PNPK和POLB）不同，这些伙伴已被证明定位于线粒体，据报道XRCC 1仅存在于细胞核中。因此，我们正在探索核到线粒体的信号传导，并检查XRCC 1的缺乏是否会促进可能导致疾病病理的线粒体功能障碍。

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.