MECHANISMS FOR REPAIR OF RADIATION DAMAGE IN HUMAN CELLS

描述：这项提议的广泛目标是阐明分子 哺乳动物细胞转录偶联修复(TCR)的机制 电离辐射和其他产生辐射的物质引起的DNA损伤 氧化损伤。先前的研究表明，TCR是一条离散的通路 用于去除阻碍转录并引导碱基的病变 对氧化损伤的切除修复(BER)。TCR需要Cockayne综合征 B组(CSB)蛋白、着色性干皮病G组(XPG)蛋白以及 XPB和XPD蛋白。对这些基因中不同等位基因的检测 揭示了它们在TCR中的功能与它们在 核苷酸切除修复(NER)和前者的缺陷与 发育障碍Cockayne综合征的临床表现。这个 这里要检验的总体假设是：(A)XPG招募的人员适当 修复阻止转录的病变的蛋白质，以及(B) 完整的TCR机器移除停滞的RNA聚合酶(RNAP)以允许修复 才会发生。对XPG蛋白质-蛋白质和蛋白质-DNA相互作用的认识 对于剖析这种蛋白质的多重功能和 将病变去除与转录相结合的分子机器。这些研究 将促进我们对细胞如何应对细胞氧化损伤的理解 转移到DNA上。

DESCRIPTION: The broad objective of this proposal is to elucidate the molecular mechanisms involved in transcription-coupled repair (TCR) in mammalian cells of DNA lesions induced by ionizing radiation and other agents that produce oxidative damage. Previous studies have shown that TCR is a discrete pathway for removal of lesions that block transcription and that it directs base excision repair (BER) to oxidative lesions. TCR requires the Cockayne syndrome group B (CSB) protein, the xeroderma pigmentosum group G (XPG) protein and also the XPB and XPD proteins. Examination of different alleles in these genes has revealed that their functions in TCR are separable from their functions in nucleotide excision repair (NER) and that defects in the former are linked to the clinical appearance of the developmental disorder Cockayne syndrome. The overall hypothesis to be tested here are that (a) XPG recruits appropriate repair proteins to lesions that are blocking transcription, and that (b) the intact TCR machinery removes the stalled RNA polymerase (RNAP) to allow repair to occur. Understanding of protein-protein and protein-DNA interactions of XPG will be important for dissecting the multiple functions of this protein and the molecular machine that couples lesion removal to transcription. These studies will advance our understanding of how cells cope with cellular oxidative damage to DNA.