STUDIES OF THE NUCLEOTIDE EXCISION REPAIR PROTEIN XPC

描述（由申请人提供）：DNA修复系统是预防癌症的重要防御。这些系统的故障会导致各种负面的生理影响，尤其是癌症。核苷酸切除修复系统是细胞对DNA损伤的关键防御机制之一，识别由紫外线阳光和来自吸烟的致癌物质产生的大体积DNA损伤。它通过识别受损的核碱基并切除含有受损核苷酸的24-32个核苷酸的DNA片段，然后合成新的DNA来取代切除的DNA。参与该系统的蛋白质是XPC-HR 23 B、XPA、RPA、TFIIH、XPG、XPF-ERCC 1、RFC、PCNA、Pol β或δ和DNA连接酶I。XPC-HR 23 B、XPA、RPA、TFIIH、XPG和XPF参与识别和切除受损DNA。RPA、TFIIH、XPG和XPF-ERCC 1除了在核苷酸切除修复中的作用外，还具有其他细胞功能，另一方面，已知XPC-HR 23 B和XPA仅在切除修复中起作用。有趣的是，XPC-HR 23 B和XPA，沿着RPA，是负责初始DNA损伤识别的蛋白质。XPA和RPA在生物化学上已经得到了很好的表征，但是对XPC-HR 23 B的功能知之甚少。该提案的目标是更好地了解XPCHR 23 B如何与受损DNA相互作用。这将通过绘制XPC-HR 23 B的DNA结合结构域并确定XPC-HR 23 B与受损DNA的详细结合动力学来实现。这些研究应该让我们深入了解XPA、RPA和XPC-HR 23 B这三种蛋白质如何识别数百种不同的DNA病变，并可能导致癌症的新治疗方法。

DESCRIPTION (provided by applicant): DNA repair systems are important defenses in the prevention of cancer. Breakdowns in these systems can lead to a variety of negative physiological effects, not least of which is cancer. The nucleotide excision repair system is one of the cell's key defense mechanisms against DNA damage, recognizing the bulky DNA lesions produced by UV sunlight and carcinogens derived from smoking. It operates by recognizing a damaged nucleobase and excising a DNA fragment of 24-32 nucleotides containing the damaged nucleotide, then synthesizing new DNA to replace the excised DNA. The proteins involved in this system are XPC-HR23B, XPA, RPA, TFIIH, XPG, XPF-ERCC1, RFC, PCNA, Pol epsilon or delta and DNA Ligase I. XPC-HR23B, XPA, RPA, TFIIH, XPG and XPF are involved in recognizing and excising the damaged DNA. RPA, TFIIH, XPG and XPF-ERCC1 all have other cellular functions besides their role in nucleotide excision repair, XPC-HR23B and XPA, on the other hand, are known to only function in excision repair. Interestingly XPC-HR23B and XPA, along with RPA, are the proteins responsible for initial DNA damage recognition. XPA and RPA have been well characterized biochemically, however less is known about how XPC-HR23B functions. The goal of this proposal will be to gain a greater understanding of how XPCHR23B interacts with damaged DNA. This will be accomplished by mapping out the DNA binding domain of XPC-HR23B and determining the detailed binding kinetics of XPC-HR23B to damaged DNA. These studies should give insight into how just three proteins, XPA, RPA and XPC-HR23B can recognize literally hundreds of different DNA lesions and may lead to new treatments for cancer.