Project 1: Base Repair: Molecular response to base-modifying chemotherapeutic agents

项目1：碱基修复：碱基修饰化疗药物的分子反应

基本信息

批准号：
10492028
负责人：
Susan Emiko Tsutakawa
金额：
$ 23.98万
依托单位：
UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-27 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10492028
关键词：
Alkylating Agents Alkylation Apoptosis Area Base Excision Repairs Biochemistry Biological Assay Biophysics Cancer Biology Cell Line Cell Survival Cells Cellular biology Cisplatin Complex Cryoelectron Microscopy Crystallography DNA DNA Damage DNA Repair DNA Repair Pathway Defect Disease Drug resistance Endoribonucleases Excision Exposure to Immune Individual Interferons Knowledge Lesion Malignant Neoplasms Measures Mediating Methods Methylation Modality Modification Molecular Neoadjuvant Therapy Nucleic Acids Nucleotides Pathway interactions Pattern Pharmacotherapy Platinum Compounds Positioning Attribute RNA Repair Complex Roentgen Rays Role Signal Pathway Signal Transduction Structure System Testing Work adduct base biophysical model cancer therapy chemotherapeutic agent chemotherapy clinically relevant clinically significant crosslink endonuclease genotoxicity helicase insight molecular modeling multidisciplinary mutant neoplastic cell novel nuclease programs repaired response structural biology therapy resistant tumor

项目摘要

SUMMARY - PROJECT 1: Molecular response to base-modifying chemotherapeutic agents Repair of base damage on DNA is critical because such damage is both genotoxic and mutagenic. Many chemotherapeutic agents used for cancer therapy, such as cisplatin and alkylating agents, induce this type of damage and are one of the most commonly used modalities for treatment, underscoring their clinical significance. While much is known about how cells respond to DNA containing base damage, the importance of RNA damage has become increasingly appreciated only recently. Indeed, alkylated RNA is estimated to comprise the vast majority of the damaged nucleic acid in cells treated with such agents. It is not surprising then that cells have evolved a number of mechanisms to cope with damaged RNA. We have discovered that the ALKBH3-ASCC repair complex mediates the cellular response to DNA as well RNA base damage. This complex also interfaces with the innate immune or DAMP (damage-associated molecular pattern) signaling through a novel RNA endonuclease activity, which we have recently uncovered through the multidisciplinary efforts of this program project. Our work implicates RNA damage recognition and signaling as a critical node in the cellular response to base damage, an underexplored area, which we seek to understand in this renewal application. Specifically, we will use a combination of structural methods and biochemistry to reveal the mechanistic basis of the enzymatic activities within the ALKBH3-ASCC complex (Aim 1). We will also determine the importance of ASCC-mediated, RNA-dependent DAMP signaling in the response to commonly used chemotherapeutic agents and its role in cell fate decisions (Aim 2). Finally, we will determine how the ALKBH3-ASCC pathway integrates with established base repair pathways, potentially identifying novel additive or synthetic lethal relationships between these pathways (Aim 3). Together, the proposed work will reveal important insights into the contribution of RNA as well as DNA base damage responses and its relevance to tumor cell eradication.

摘要 - 项目 1：对碱基修饰化疗药物的分子反应 DNA 碱基损伤的修复至关重要，因为这种损伤既具有遗传毒性又具有诱变性。许多用于癌症治疗的化疗药物，例如顺铂和烷化剂，会诱导这种类型的损伤，是最常用的治疗方式之一，强调了其临床意义。虽然人们对细胞如何响应含有碱基损伤的 DNA 知之甚多，但 RNA 损伤的重要性直到最近才变得越来越受重视。事实上，据估计，烷基化 RNA 包含大量用此类试剂处理的细胞中的大部分核酸被破坏。那么细胞具有进化出许多机制来应对受损的RNA。我们发现 ALKBH3-ASCC 修复复合物介导细胞对 DNA 和 RNA 碱基损伤的反应。这个综合体还接口通过新型 RNA 进行先天免疫或 DAMP（损伤相关分子模式）信号传导我们最近通过该计划的多学科努力发现了核酸内切酶活性项目。我们的工作表明 RNA 损伤识别和信号传导是细胞响应的关键节点基础损坏是一个尚未开发的领域，我们希望在此更新申请中了解这一点。具体来说，我们将结合结构方法和生物化学来揭示酶促作用的机制基础 ALKBH3-ASCC 复合体内的活动（目标 1）。我们还将确定 ASCC 介导的重要性， RNA依赖性DAMP信号传导对常用化疗药物的反应及其在细胞中的作用命运决定（目标 2）。最后，我们将确定 ALKBH3-ASCC 通路如何与已建立的碱基修复途径，有可能识别这些之间的新的加成或合成致死关系途径（目标 3）。总之，拟议的工作也将揭示有关 RNA 贡献的重要见解 DNA 碱基损伤反应及其与肿瘤细胞根除的相关性。