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. Significance: 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, [p. 23][1] . This article is highlighted in the In This Issue feature, [p. 1][2] [1]: /lookup/volpage/12/23?iss=1 [2]: /lookup/volpage/12/1?iss=1

中文翻译：

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DNMT3A 变体的系统分析揭示了由 DCAF8 E3 泛素连接酶适配器介导的蛋白质不稳定性

克隆性造血是一种普遍的与年龄相关的疾病，与血液系统疾病的风险大大增加有关。DNA 甲基转移酶 3A (DNMT3A) 的突变是这种状态最常见的驱动因素。DNMT3A 变异发生在整个基因中，其中一些与恶性肿瘤特别相关，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 个与疾病相关的 DNMT3A 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降低的蛋白质稳定性，并且作为一个类别，与更大的克隆扩增和急性髓性白血病的发展相关。我们使用 CRISPR 筛选研究了不稳定性背后的机制，并发现了由 DCAF8 E3 泛素连接酶接头介导的 DNMT3A 的调节破坏。我们建立了一种新的范式来分类对血液病患者具有预后和潜在治疗意义的新变体。意义：DNMT3A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 DNMT3A 错义突变的分子影响，并发现了 DNMT3A 的调节破坏机制，提供了新的预后和未来治疗途径。见 Ma 和 Will 的相关评论，[p. 23][1]。本文在 In This Issue 功能中突出显示，[p. 1][2][1]：