Methyltransferase Contributions to Genomic Stability and Cancer

摘要 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，几乎没有有效的治疗选择，并且高度耐药。 许多传统疗法。最近在这种癌症中的一个发现是组蛋白SETD 2的高频突变， 甲基转移酶，是唯一负责将组蛋白H3赖氨酸36（H3 K36 me 3） 三甲基化标记活跃转录基因。我们的两个小组同时进行了一系列非常 与SETD 2甲基转移酶作为肿瘤抑制剂的新作用有关的令人兴奋的发现 基因组稳定性所必需的。首先，我们观察到染色质上H3 K36 me 3标记的缺失损害了 修复DNA双链断裂。这表明SETD 2的缺失导致了DNA修复缺陷，我们认为这是一种基因缺陷。 假设是由于错误定向的H3 K36 me 3“读者”，通常会引导DNA修复机制， 双链断裂，导致基因组不稳定。独立地说，我们最近有了令人兴奋的发现 一个重要的新的非组蛋白目标的SETD 2甲基转移酶：微管。这些数据显示 有丝分裂微管的赖氨酸40（K40 Me）上的α-微管蛋白的SETD 2甲基化是正常细胞增殖所必需的。 染色体分离和胞质分裂，为理解SETD 2的丢失如何贡献 基因组不稳定性和肾细胞癌进展的一个全新的方式。我们提出了一个多方面的 合作项目，以了解1）如何设置2作为一个组蛋白和微管甲基转移酶的功能 有助于基因组的稳定性和RCC的发展2）连接组蛋白甲基化的机制 缺陷的DNA双链断裂修复缺陷，和3）利用我们所知道的这种酶和 破坏生物学，以确定药理学工具化合物，我们将在体内测试，以探索关键 基因组维持的生物学特性或对未来靶向治疗有希望。

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.