Systematic Profiling of DNMT3A Variants Reveals Protein Instability Mediated by the DCAF8 E3 Ubiquitin Ligase Adaptor.
Systematic Profiling of DNMT3A Variants Reveals Protein Instability Mediated by the DCAF8 E3 Ubiquitin Ligase Adaptor.
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DOI：
10.1158/2159-8290.cd-21-0560
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发表时间：
2022-01
期刊：
影响因子：
28.2
通讯作者：
Goodell MA
中科院分区：
文献类型：
--
作者：
Huang YH;Chen CW;Sundaramurthy V;Słabicki M;Hao D;Watson CJ;Tovy A;Reyes JM;Dakhova O;Crovetti BR;Galonska C;Lee M;Brunetti L;Zhou Y;Tatton-Brown K;Huang Y;Cheng X;Meissner A;Valk PJM;Van Maldergem L;Sanders MA;Blundell JR;Li W;Ebert BL;Goodell MA
DNMT 3A变体的分析揭示了大部分DNA甲基转移酶活性和蛋白质稳定性的急剧丧失，这使得恶性肿瘤发展的风险分层成为可能，并揭示了调节DNMT 3A周转的分子机制。克隆性造血是一种普遍的年龄相关疾病，与血液病风险大大增加相关; DNA甲基转移酶3A（DNMT 3A）突变是这种状态最常见的驱动因素。DNMT 3A变异发生在整个基因中，其中一些特别与恶性肿瘤相关，但大多数突变的功能相关性和发病机制尚不清楚。在这里，我们系统地研究了253个疾病相关的DNMT 3A突变的甲基转移酶活性和蛋白质稳定性，发现74%是功能丧失突变。这些变体中有一半表现出蛋白质稳定性降低，并且作为一类，与更大的克隆扩增和急性髓性白血病发展相关。我们使用CRISPR筛选研究了不稳定性的潜在机制，并发现了DCAF 8 E3遍在蛋白连接酶衔接子介导的DNMT 3A的调节破坏。我们建立了一个新的范式来分类新的变异，对血液病患者具有预后和潜在的治疗意义。DNMT 3A已成为造血系统中最重要的表观遗传调节因子和肿瘤抑制因子。我们的研究代表了一种系统和高通量的方法来表征DNMT 3A错义突变的分子影响，并发现了DNMT 3A的调节破坏机制，提供了新的预后和未来的治疗途径。 参见Ma和Will的相关评论。 这篇文章在本期专题中突出显示，
Profiling of DNMT3A variants revealed a large portion with dramatic loss of DNA methyltransferase activity and protein stability, which enabled the risk stratifi cation of malignancy development and revealed a molecular mechanism of regulated DNMT3A turnover. Clonal hematopoiesis is a prevalent age-related condition associated with a greatly increased risk of hematologic disease; mutations in DNA methyltransferase 3A (DNMT3A) are the most common driver of this state. DNMT3A variants occur across the gene with some particularly associated with malignancy, but the functional relevance and mechanisms of pathogenesis of the majority of mutations are unknown. Here, we systematically investigated the methyltransferase activity and protein stability of 253 disease-associated DNMT3A mutations, and found that 74% were loss-of-function mutations. Half of these variants exhibited reduced protein stability and, as a class, correlated with greater clonal expansion and acute myeloid leukemia development. We investigated the mechanisms underlying the instability using a CRISPR screen and uncovered regulated destruction of DNMT3A mediated by the DCAF8 E3 ubiquitin ligase adaptor. We establish a new paradigm to classify novel variants that has prognostic and potential therapeutic significance for patients with hematologic disease. DNMT3A has emerged as the most important epigenetic regulator and tumor suppressor in the hematopoietic system. Our study represents a systematic and high-throughput method to characterize the molecular impact of DNMT3A missense mutations and the discovery of a regulated destruction mechanism of DNMT3A offering new prognostic and future therapeutic avenues. See related commentary by Ma and Will, . This article is highlighted in the In This Issue feature,