Methyltransferase Contributions to Genomic Stability and Cancer

摘要 肾细胞癌(RCC)是研究表观遗传调控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，并且对 很多传统疗法。这种癌症的一个最新发现是组蛋白SETD2的高频突变 甲基转移酶，是唯一负责将组蛋白H3赖氨酸36(H3K36me3) 活跃转录基因上的三甲基化标记。我们两个小组同时制定了一系列非常 与SETD2甲基转移酶作为肿瘤抑制因子的新角色有关的令人兴奋的发现 是基因组稳定所必需的。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的丢失会导致DNA修复缺陷，我们 假设是由于错误地定向了H3K36me3读取器，通常会引导DNA修复机器 双链断裂，导致基因组不稳定。独立地，我们最近有了一个令人兴奋的发现 SETD2甲基转移酶的一个重要的新的非组蛋白靶标：微管。这些数据表明， α-微管蛋白在有丝分裂微管赖氨酸40(K40Me)上的SETD2甲基化是正常的 染色体分离和胞质分裂，为理解SETD2的缺失是如何起作用的打开了大门 以一种全新的方式对肾癌的基因组不稳定性和进展进行研究。我们提出了一个多方面的 了解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 有助于基因组的稳定和肾癌的发展2)组蛋白甲基化的机制 DNA双链断裂修复缺陷，以及3)利用我们所知的这种酶和 破坏生物学以鉴定药理工具化合物，我们将在体内测试这些化合物以探索关键 基因组维持的生物学特性或为未来的靶向治疗带来希望的生物学特性。

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.