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The RAP80-BRCC36 Deubiquitinating Complex in DNA Repair

DNA 修复中的 RAP80-BRCC36 去泛素化复合物

基本信息

批准号：
9099237
负责人：
Roger A Greenberg
金额：
$ 4万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9099237
关键词：
Affect Architecture BRCA1 Protein BRCA1 gene BRCA2 gene Binding Biochemical Biochemistry Cancer Etiology Cells Cellular Structures Cellular biology Chromatin Comb animal structure Complex DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway DNA crosslink Deubiquitinating Enzyme Deubiquitination Disabled Persons Enzyme Inhibition Excision Fanconi anemia protein Fanconi&apos s Anemia Fiber Functional disorder Genes Genetic Genetic Epistasis Genetic screening method Genetically Engineered Mouse Genomic Instability Hematopoietic Hereditary Breast Carcinoma Higher Order Chromatin Structure Human Hydrolysis Hypersensitivity In Vitro Inherited Knockout Mice Link Maintenance Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of pancreas Malignant neoplasm of prostate Mediator of activation protein Mitomycins Molecular Multienzyme Complexes Mus Mutate Mutation Null Lymphocytes Predisposition Process Proteins Research Role S Phase Site Specificity Stress Structure Testing Tumor Suppression Tumor Suppressor Proteins Ubiquitin Work X-Ray Crystallography base cancer therapy chemotherapy crosslink enzyme activity genome integrity homologous recombination in vivo insight malignant breast neoplasm member molecular imaging mouse model mutant protein complex public health relevance recombinational repair repaired research study response

项目摘要

DESCRIPTION (provided by applicant): Inherited mutations in the Breast Cancer 1 and 2 genes (BRCA1 and BRCA2) confer susceptibility to breast and ovarian cancer, as well as to pancreatic and prostate cancers. The BRCA proteins are required for DNA repair by homologous recombination and this function is intimately connected to tumor suppression. BRCA mutation status is also an important predictor of response to chemotherapy. Inhibition of specific DNA repair pathways has emerged as an elegant and effective strategy to induce synthetic lethality in BRCA mutant cancers. Understanding the molecular basis of BRCA dependent DNA repair is therefore a central issue to cancer etiology and therapy. We have discovered that BRCA1 is targeted to lysine63-linked ubiquitin regions aligning DNA double-strand break chromatin by the RAP80-BRCC36 complex. Deficiency of this complex results in reduced BRCA1 DNA damage localization and genomic instability. Moreover, mutations within several genes that encode constituents of this complex are associated with familial breast cancer. This indicates that ubiquitin recognition at double-strand break chromatin is a bona fide component of BRCA dependent tumor suppression. This proposal will take in vivo, cellular, and structure guided biochemical approaches to understand how DNA double-strand break ubiquitin recognition by the RAP80-BRCC36 complex relates to BRCA dependent homologous recombination repair mechanisms and response to therapy. The studies are intended to elucidate basic DNA repair mechanisms and gain insights into cancer etiology and therapy.

描述（由申请人提供）：乳腺癌1和2基因（BRCA 1和BRCA 2）的遗传突变赋予乳腺癌和卵巢癌以及胰腺癌和前列腺癌的易感性。BRCA蛋白是通过同源重组进行DNA修复所必需的，并且该功能与肿瘤抑制密切相关。BRCA突变状态也是化疗反应的重要预测因子。抑制特定的DNA修复途径已成为一种优雅而有效的策略，以诱导BRCA突变型癌症的合成致死性。因此，了解BRCA依赖性DNA修复的分子基础是癌症病因学和治疗的核心问题。我们发现BRCA 1通过RAP 80-BRCC 36复合物靶向于赖氨酸63连接的泛素区域，对齐DNA双链断裂染色质。这种复合物的缺乏导致BRCA 1 DNA损伤定位和基因组不稳定性降低。此外，编码该复合物成分的几个基因内的突变与家族性乳腺癌相关。这表明在双链断裂染色质处的泛素识别是BRCA依赖性肿瘤抑制的真正组成部分。该提案将采用体内、细胞和结构指导的生物化学方法来了解RAP 80-BRCC 36复合物对DNA双链断裂泛素的识别如何与BRCA依赖性同源重组修复机制和对治疗的反应相关。这些研究旨在阐明基本的DNA修复机制，并深入了解癌症病因和治疗。