Methyltransferase Contributions to Genomic Stability and Cancer

甲基转移酶对基因组稳定性和癌症的贡献

基本信息

批准号：
9130344
负责人：
WENDY KIMRYN RATHMELL
金额：
$ 44.09万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9130344
关键词：
Acute Angiogenesis Inhibitors Biological Biology Chromatin Chromosome Segregation Chromosomes Coupling Cytokinesis DNA Damage DNA Double Strand Break DNA Repair DNA Sequence Alteration Data Defect Development Double Strand Break Repair Enzymes Epigenetic Process Epithelial Frequencies Future Genes Genetic Transcription Genome Genome Stability Genomic Instability Genomics HDAC6 gene Histone H3 Histones Human Intervention Left Link Loss of Heterozygosity Lysine Maintenance Malignant Neoplasms Measurable Metastatic Renal Cell Cancer Methylation Methyltransferase Microtubules Mitotic Mitotic spindle Modification Mono-S Mutate Mutation Pathway interactions Pattern Phenotype Phosphoric Monoester Hydrolases Phosphotransferases Prevention Process Property Reader Renal Cell Carcinoma Resistance Role Series Signal Transduction Source Stream Testing Therapeutic Tubulin Tumor Suppressor Proteins alpha Tubulin base cancer cell chemical genetics chemotherapy design effective therapy gene repair histone methylation histone methyltransferase in vivo insight micronucleus mutant novel novel therapeutics open data prototype repaired segregation targeted treatment tool traditional therapy tumor tumor progression

项目摘要

ABSTRACT Renal cell carcinoma (RCC) is a prototype for the study of epigenetic regulators as major drivers of the cancer phenotype. It is also a notable as a cancer with few effective treatment options, and high degree resistance to many traditional therapies. One recent discovery in this cancer is high frequency mutation of SETD2, a histone methyltransferase that is the sole enzyme responsible for placing the histone H3 lysine 36 (H3K36me3) trimethylation mark on actively transcribed genes. Our two groups have in parallel made a series of very exciting discoveries related to a new role for the SETD2 methyltransferase as a tumor suppressor required for genomic stability. First, we observed that loss of the H3K36me3 mark on chromatin impairs repair of DNA double strand breaks. This suggests that loss of SETD2 causes a DNA repair defect, which we hypothesize is due to mis-directed H3K36me3 “readers” that would normally guide DNA repair machinery to double strand breaks, resulting in genomic instability. Independently, we recently made the exciting discovery of an important novel nonhistone target for the SETD2 methyltransferase: microtubules. These data show that SETD2 methylation of α-tubulin on lysine 40 (K40Me) of mitotic microtubules is required for proper chromosome segregation and cytokinesis, opening the door for understanding how loss of SETD2 contributes to genomic instability and progression of RCC in a completely new way. We are proposing a multifaceted collaborative project to understand 1) how SETD2 function as a histone and microtubule methyltransferase contributes to genomic stability, and the development of RCC 2) the mechanism linking histone methylation deficits to DNA double strand break repair deficiency, and 3) exploit what we know of this enzyme and the biology of disruption to identify pharmacologic tool compounds, which we will test in vivo for exploring key biological properties of genome maintenance or which hold promise for future targeted therapeutics.

抽象的肾细胞癌（RCC）是研究表观遗传调节剂作为癌症的主要驱动因素的原型表型。它也是一个著名的是癌症，几乎没有有效的治疗选择，并且对许多传统疗法。该癌症中最近发现的一个是组蛋白的高频突变甲基转移酶是负责放置组蛋白H3赖氨酸36（H3K36ME3）的唯一酶主动转录基因上的三甲基化标记。我们的两个小组并行了一系列非常与SETD2甲基转移酶的新作用相关的令人兴奋的发现作为肿瘤抑制剂基因组稳定性所必需的。首先，我们观察到染色质上H3K36me3标记的丢失 DNA双链断裂的修复。这表明setD2的损失会导致DNA修复缺陷，我们假设是由于未指导的H3K36me3“读取器”，通常将DNA修复机器引导到双链断裂，导致基因组不稳定性。独立地，我们最近做出了令人兴奋的发现 SETD2甲基转移酶的重要新型非组蛋白靶标的：微管。这些数据表明赖氨酸40（K40me）在丝裂微微皮蛋白上的α-微管蛋白的SETD2甲基化是正确的染色体分离和细胞因子，为了解SETD2的损失如何贡献开辟了大门以一种全新的方式来实现RCC的基因组不稳定性和进展。我们提出了一个多方面的合作项目以了解1）SETD2如何作为组蛋白和微管甲基转移酶的功能有助于基因组稳定性以及RCC的发展2）连接组蛋白甲基化的机制 DNA双链断裂修复缺陷的缺陷，3）利用我们对此酶的了解和识别药物学工具化合物的破坏生物学，我们将在体内测试探索密钥基因组维持的生物学特性或对未来靶向疗法有望有望。