CELLULAR RESPONSES TO UV-LIGHT IN ATAXIA TELANGIECTASIA

描述：（改编自研究者摘要）申请人建议 研究人类遗传性疾病共济失调的分子基础 毛细血管扩张（A-T）。A-T是一种常染色体隐性遗传病 特征为进行性小脑共济失调，眼皮肤毛细血管扩张， 对电离辐射的敏感性增强，癌症风险增加。在 此外，患者表现出免疫缺陷，过早衰老的迹象， 某些器官和组织发育不全。申请人将专注于 A-T患者的细胞对DNA损伤剂的明显异常反应。 申请人假设这种异常反应导致增强的 与疾病相关的遗传不稳定性。申请人专注于 A-T细胞对DNA损伤反应的两种异常： 磷酸化某些关键蛋白质（如RPA）;以及DNA的异常修复 双链断裂他们提出了ATM在这些领域中的作用模型。 反应：DNA链断裂是在DNA的异常复制过程中产生的。 紫外线损伤的DNA模板; ATM与DNA末端结合，激活蛋白激酶 并保护末端免于过度降解; ATM使RPA磷酸化， 降低RPA对ssDNA的亲和力并促进链配对 在DSB修复期间。目的是了解A-T缺陷如何导致 增强了基因组对紫外线和红外线的不稳定性。 （1）确定紫外线诱导的功能性后果 RPA过度磷酸化。(2)要确定ATM是否直接参与 DSB修复。(3)为了确定ARM介导的RPA过度磷酸化是否 在DSB修复中起作用。(4)确定ATM在UV诱导的RPA中的作用 过度磷酸化本项目的最终目标是定义 A-T细胞对UV/IR反应的潜在缺陷，希望这一点 理解将导致治疗这种疾病的策略的发展， 一种毁灭性的遗传性神经疾病

DESCRIPTION: (Adapted from the investigator's abstract) The applicant proposes to investigate the molecular basis of the human genetic disease, ataxia telangiectasia (A-T). A-T is an autosomal recessive human genetic disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, enhanced sensitivity to ionizing radiation and increased cancer risk. In addition, patients exhibit immune deficiencies, signs of premature aging and underdevelopment of certain organs and tissues. The applicant will focus on the apparent abnormal response of cells from A-T patients to DNA-damaging agents. The applicant postulates that this abnormal response leads to the enhanced genetic instability associated with the disease. The applicants have focused on two abnormalities in the response of A-T cells to DNA damage: failure to phosphorylate certain key proteins (e.g. RPA); and abnormal repair of DNA double-strand breaks. They propose a model for the role of ATM in these responses: DMA strand breaks are produced during aberrant replication of UV-damaged DNA templates; ATM binds to DNA ends, activating the protein kinase and protection the ends from excessive degradation; ATM phosphorylates RPA, reducing the affinity of RPA for ssDNA and facilitating the pairing of strands during DSB repair. The goal is to understand how the A-T defect leads to enhanced genomic instability in response to UV and IR. The specific aims of this project are: (1) To determine the functional consequences of UV-induced RPA hyperphosphorylation. (2) To determine whether ATM participates directly in DSB repair. (3) To determine whether ARM-mediated RPA hyperphosphorylation plays a role in DSB repair. (4) To determine the role of ATM in UV-induced RPA hyperphosphorylation. The ultimate goal of this project is to define the underlying defect in the response of A-T cells to UV/IR with the hope that this understanding will lead to the development of strategies for treating this devastating genetic neurological disease of childhood.