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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：
9518574
负责人：
WENDY KIMRYN RATHMELL
金额：
$ 43.29万
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/9518574
关键词：
Acute Alleles Angiogenesis Inhibitors Biological Biology C-terminal Carcinoma Chromatin Chromatin Remodeling Factor 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 Frequencies Future Genes Genetic Transcription Genome Genome Stability Genomic Instability Genomics HDAC6 gene Histone H3 Histones Human Impairment 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 Pharmacology 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 druggable target effective therapy gene repair histone methylation histone methyltransferase in vivo in vivo evaluation insight mutant novel novel therapeutics open data prototype 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因子作为癌症主要驱动因素的原型表型。它也是一种值得注意的癌症，有效的治疗选择很少，而且对癌症的抵抗力很高。许多传统疗法。最近在这种癌症中发现的一项发现是 SETD2（一种组蛋白）的高频突变甲基转移酶是负责将组蛋白 H3 赖氨酸 36 (H3K36me3) 放置的唯一酶活跃转录基因上的三甲基化标记。我们的两个小组同时制作了一系列非常与 SETD2 甲基转移酶作为肿瘤抑制因子的新作用相关的令人兴奋的发现基因组稳定性所需的。首先，我们观察到染色质上 H3K36me3 标记的丢失会损害 DNA双链断裂的修复。这表明 SETD2 的缺失会导致 DNA 修复缺陷，我们对此进行了研究。假设是由于 H3K36me3“读者”的误导，通常会引导 DNA 修复机制双链断裂，导致基因组不稳定。我们最近独立地做出了令人兴奋的发现 SETD2 甲基转移酶的一个重要的新型非组蛋白靶标：微管。这些数据表明有丝分裂微管的赖氨酸 40 (K40Me) 上的 α-微管蛋白的 SETD2 甲基化是适当的染色体分离和胞质分裂，为了解 SETD2 缺失如何发挥作用打开了大门以全新的方式控制基因组不稳定性和肾细胞癌的进展。我们提出了多方面的建议了解 1) SETD2 如何作为组蛋白和微管甲基转移酶发挥作用的合作项目有助于基因组稳定性和 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，以及 3）利用我们对这种酶和破坏生物学以确定药理工具化合物，我们将在体内进行测试以探索关键基因组维护的生物学特性或为未来的靶向治疗带来希望。