DNA错配修复的表观调控机制及其在癌症发生中的作用

DNA mismatch repair (MMR) maintains genome fidelity by correcting mismatches generated during DNA replication. Defects in MMR genes lead to cancers. A characteristic of MMR-deficient cancers is their ability to display frequent alterations in simple repetitive DNA sequences, a phenomenon called microsatellite instability (MSI). However, a subset of MSI-positive cancers do not carry a detectable mutation in MMR genes. Recent studies have implicated epigenetic factors in MMR. First, histone H3 Lys36 trimethylation (H3K36me3) is essential for MMR by recruiting MMR proteins to chromatin, and frequent SETD2 mutations and H3.3G34V/R mutations were identified in glioblastoma and other cancers. Since SETD2 catalyzes H3K36 trimethylation and the bulky side chains resulted from G34V/R mutations may block H3K36 interactions with SETD2 and MMR proteins, we hypothesize that these mutations lead to MMR deficiency and tumorigenesis. Second, increasing evidence suggests an involvement of long non-coding RNAs (LncRNAs) in etiology of MSI-positive colorectal cancer, but the mechanism is unknown. In this application, we will combine biochemistry, molecular biology and cell biology approaches to study the mechanism by which H3G34V/R mutations impair MMR function, and identify as well as characterize LncRNAs that regulate the MMR system, and their implication in cancer susceptibility. A successful completion of this project will provide new epigenetic mechanisms for MMR regulation, new biomarkers and targets for cancer detection and therapy.

DNA错配修复 (MMR)维持DNA复制的保真性。MMR基因缺陷导致基因突变和癌变，其显著特征之一是微卫星不稳定性 (MSI)。然而部分MSI阳性的癌并没有MMR基因缺陷。我们最近发现SETD2介导的组蛋白修饰H3K36me3是体内MMR的重要调控因子。癌基因组测序揭示，SETD2突变和H3.3G34V/R突变导致恶性胶质瘤。我们推测H3.3G34V/R通过阻断SETD2对H3K36甲基化和H3K36me3与MMR蛋白的互作来抑制MMR，从而促进癌变。另有研究报道MSI阳性癌与长链非编码RNA (LncRNA)有关；我们未发表的研究也发现MMR影响LncRNA表达。因此，我们推测LncRNA参与调控MMR与癌变。本研究将探究H3突变调控MMR的机制，筛选调控MMR的LncRNA并研究作用机制，从而对调控MMR的表观机制进行全面解析，并为相关癌的病理提供新的解释，为其诊治提供新的思路和靶标。

DNA错配修复维持DNA复制的保真性。MMR基因缺陷导致基因突变和癌变，其主要特征之一是微卫星不稳定性。由于部分MSI阳性的癌并没有MMR基因缺陷，我们发现SETD2介导的组蛋白修饰H3K36me3是体内MMR的重要调控因子。通过癌基因组测序揭示，SETD2突变和H3.3G34V/R突变导致恶性胶质瘤。我们证明了H3.3G34V/R通过阻断SETD2对H3K36甲基化和H3K36me3与MMR蛋白的互作来抑制MMR，从而促进癌变。同时揭示了H3K36me3相关组蛋白突变 H3G34V/R/D通过影响H3K36me3修饰及其与错配识别蛋白MutSα的相互作用来调控体内MMR功能，进而影响恶性胶质瘤发生。另有我们的研究也发现MMR影响LncRNA表达。同时筛选LncRNA ANCR调控MMR机制的研究。总之，我们的研究对调控MMR的表观机制进行全面解析，并为相关癌的病理提供新的解释，为其诊治提供新的思路和靶标。