Base Excision DNA Repair in Disease Susceptibility and Treatment

利用分子、生化和结构方法，我们已经帮助定义了人类BER蛋白如何识别和协调处理目标病变。该研究集中在两种蛋白APE1和XRCC1上，APE1是修复DNA基本位点的主要哺乳动物蛋白，XRCC1是一种非酶支架，促进单链断裂修复的有效执行。实验室的主要基础科学目标之一是建立转基因细胞系，以解剖APE1在细胞生长/活力，基因组维持和防止dna损伤剂方面的每种功能（即其核酸酶活性，氧化还原调节作用等）的精确贡献。在众多已报道的APE1功能中，确定哪些功能对正常细胞活动至关重要，是理解该蛋白与衰老过程和疾病风险之间潜在关系的关键一步。

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.