MECHANISMS FOR REPAIR OF RADIATION DAMAGE IN HUMAN CELLS

描述：本提案的主要目的是阐明 转录偶联修复（TCR）在哺乳动物细胞中的机制， 电离辐射和其他产生电离辐射的物质引起的DNA损伤 氧化损伤以往的研究表明，TCR是一个离散的途径， 用于去除阻断转录的病变， 切除修复（BER）氧化损伤。TCR需要Cockayne综合征 B组（CS B）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），前者的缺陷与 发育障碍科凯恩综合征的临床表现的 这里要检验的总体假设是：（a）XPG招募适当的 修复蛋白质的损伤，阻断转录，和（B）， 完整的TCR机制去除了停滞的RNA聚合酶（RNAP）， 发生。对XPG蛋白质-蛋白质和蛋白质-DNA相互作用的理解 将是重要的解剖这种蛋白质的多种功能， 一种将损伤去除与转录结合起来的分子机器。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 到DNA

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.