The role of DNA repair in retroviral infection

描述(申请人提供)：DNA修复在逆转录病毒感染中的作用这项建议的目标是研究两条明确定义的宿主DNA修复途径，它们作为逆转录病毒感染的积极和消极调节因素。我们以前的研究已经确定核苷酸切除修复(NER)基因XPB(ERCC3)和XPD(ERCC2)是主要的逆转录病毒cDNA降解途径的核心角色，该途径消除了很大一部分进入的cDNA，并负责显著降低整合的频率(阴性逆转录病毒调节因子)。在最近的研究中，我们发现了碱基切除修复(BER)途径基因，这些基因可以显着提高整合效率(阳性逆转录病毒调节因子)。这两种DNA修复途径都在逆转录和整合完成后相对未被探索的阶段影响逆转录病毒的生命周期。我们建议研究这两条DNA修复途径对逆转录病毒感染的调控机制，有以下两个具体目的：1)明确TFIIH介导的逆转录病毒c DNA降解途径的组成和作用机制。阐明BER蛋白在逆转录病毒整合中的作用。这些目标将使用包括遗传和生化方法在内的实验策略来实现。了解这些逆转录病毒感染的正负调控因子的机制可能是未来抗逆转录病毒治疗的基础。公共卫生相关性：逆转录病毒，包括艾滋病毒和HTLV逆转录病毒家族，对公共卫生构成重大和持续的威胁。这些研究旨在阐明抵抗逆转录病毒感染的固有细胞内宿主防御和有效逆转录病毒感染所需的宿主蛋白途径。这两条途径似乎都有潜力被开发为未来新型抗逆转录病毒疗法的靶点。

DESCRIPTION (provided by applicant): The Role of DNA Repair in Retroviral Infection The goal of this proposal is to examine two well-defined host DNA repair pathways that act as positive and negative regulators of retroviral infection. Our previous studies have identified the Nucleotide Excision Repair (NER) genes XPB(ERCC3) and XPD(ERCC2) as central players in a major retroviral cDNA degradation pathway that eliminates a substantial portion of the incoming cDNAs, and is responsible for significantly reducing the frequency of integration (negative retrovirus regulators). In more recent studies we have identified Base Excision Repair (BER) pathway genes that significantly enhance the efficiency of integration (positive retrovirus regulators). Both DNA repair pathways affect the retroviral life cycle at the relatively unexplored stages following reverse transcription and through completion of integration. We propose to examine the regulatory mechanisms of these two DNA repair pathways on retroviral infection with the following two specific aims: 1.) to define the components and mechanism of TFIIH mediated retroviral cDNA degradation pathway, and 2.) to elucidate the role of BER proteins on retroviral integration. These aims will be accomplished using experimental strategies that include both genetic and biochemical approaches. Understanding the mechanisms of these positive and negative regulators of retroviral infection may be the foundation for future anti-retroviral therapies. PUBLIC HEALTH RELEVANCE: Retroviruses, including HIV and the family of HTLV retroviruses, present a significant and continuing threat to public health. These studies aim at elucidating both an innate intracellular host defense against retroviral infection and a pathway of host proteins required for efficient retroviral infection. Both pathways appear to possess the potential to be exploited as targets for future novel anti-retroviral therapies.