GENETIC AND GENOMIC RESPONSES TO DNA DAMAGE

对 DNA 损伤的遗传和基因组反应

• 批准号: 6377105
• 负责人: CHARLES M RUDIN
• 金额: $ 12.97万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6377105
• 关键词: DNA damage; antineoplastics; apoptosis; biological signal transduction; cell growth regulation; cell line; chemical carcinogenesis; chromosome aberrations; complementary DNA; drug adverse effect; gene induction /repression; genetic library; radiation carcinogenesis; transcription factor; transposon /insertion element

As more successful therapy for certain cancers has evolved, secondary malignancy has become an increasingly important concern. In addition, recent progress in supportive care for patients undergoing high dose chemotherapy, with hematopoietic growth factors or hematopoietic system cell support, has led to a dramatic increase in the number of patients treated with prolonged and high dose DNA-damaging therapy. A method for studying the molecular effects of such therapy has been designed using cells made resistant to programmed cell death by overexpression of the apoptotic inhibitor Bcl-xL. Differential mRNA display has been used to compare gene expression in the presence and absence of chemotherapeutic agents with various mechanisms of action. This technique has resulted in the identification of a number of transcripts specifically upregulated by prolonged exposure to DNA-damaging chemotherapy. Among the transcripts identified are members of a family of retrotransposable elements. The role of mobile elements and of other transcripts identified by this technique in the cellular response to DNA damage will be explored. Programmed cell death is a critical defense mechanism against the continued proliferation of cells suffering major DNA damage or chromosomal aberrancy. Major genomic rearrangements and aneuploidy are frequent events in cancer, suggesting that the signaling pathway from DNA damage to programmed cell death is defective in the majority of cancer cells. Defects in this response pathway may be critical in permitting the genomic alterations involved in carcinogenic transformation. A genetic screen for factors involved in this apoptotic signaling pathway is being performed using a retroviral cDNA library in mammalian cells exposed to DNA-damaging agents. Exposure to DNA-damaging chemotherapy is associated with induction of programmed cell death, or apoptosis, in chemosensitive tumors. Exposure to these agents has also been associated with characteristic chromosomal rearrangements of secondary malignancies. This proposal seeks to better define both of these molecular pathways, from DNA damage to programmed cell death, and from DNA damage to chromosomal aberrancy. Understanding the molecular basis of the various cellular responses to DNA damage is relevant to the design of both chemopreventative and therapeutic anticancer strategies.

随着对某些癌症更成功的治疗方法的发展，继发性恶性肿瘤已成为越来越重要的问题。 此外，最近在支持性护理方面取得的进展，对接受高剂量化疗的患者进行造血生长因子或造血系统细胞支持，导致接受长期和高剂量DNA损伤治疗的患者数量急剧增加。 已经设计了一种研究这种治疗的分子效应的方法，使用通过过表达凋亡抑制剂Bcl-xL而对程序性细胞死亡具有抗性的细胞。 差异mRNA显示已被用于比较基因表达的存在和不存在的化疗药物与各种作用机制。 该技术已导致鉴定了一些转录本，这些转录本通过长时间暴露于DNA损伤化疗而特异性上调。在转录本中确定的是一个家庭的成员反转录转座因子。 移动的元素和其他转录本确定的细胞响应DNA损伤的这种技术的作用将进行探讨。程序性细胞死亡是防止遭受重大DNA损伤或染色体异常的细胞持续增殖的关键防御机制。 主要的基因组重排和非整倍体是癌症中常见的事件，表明从DNA损伤到程序性细胞死亡的信号传导途径在大多数癌细胞中是有缺陷的。 在这个反应途径的缺陷可能是关键的允许致癌转化涉及的基因组改变。 一个基因筛选的因素参与这一凋亡信号通路正在进行使用的逆转录病毒cDNA文库在哺乳动物细胞暴露于DNA损伤剂。 在化疗敏感的肿瘤中，暴露于DNA损伤化疗与诱导程序性细胞死亡或凋亡相关。 暴露于这些药物也与继发性恶性肿瘤的特征性染色体重排有关。 该提案旨在更好地定义这两种分子途径，从DNA损伤到程序性细胞死亡，以及从DNA损伤到染色体异常。 了解DNA损伤的各种细胞反应的分子基础与化学预防和治疗性抗癌策略的设计有关。