Polycomb 靶点的癌症相关 DNA 高甲基化需要 DNMT3A 对组蛋白 H2AK119 泛素化和核小体酸性补丁的双重识别。
Cancer-associated DNA hypermethylation of Polycomb targets requires DNMT3A dual recognition of histone H2AK119 ubiquitination and the nucleosome acidic patch.
发表日期：2024 Aug 30
作者：
Kristjan H Gretarsson, Stephen Abini-Agbomson, Susan L Gloor, Daniel N Weinberg, Jamie L McCuiston, Vishnu Udayakumar Sunitha Kumary, Allison R Hickman, Varun Sahu, Rachel Lee, Xinjing Xu, Natalie Lipieta, Samuel Flashner, Oluwatobi A Adeleke, Irina K Popova, Hailey F Taylor, Kelsey Noll, Carolina Lin Windham, Danielle N Maryanski, Bryan J Venters, Hiroshi Nakagawa, Michael-Christopher Keogh, Karim-Jean Armache, Chao Lu
来源：
GENES & DEVELOPMENT
摘要：
在肿瘤发展过程中，通常被 Polycomb 抑制复合物 (PRC) 沉默的启动子 CpG 岛变得 DNA 高甲基化。从头 DNA 甲基转移酶 [DNMT] 在 PRC 调控区域催化 CpG 甲基化的分子机制仍不清楚。在这里，我们报道了 DNMT3A 长亚型 (DNMT3A1) 氨基末端区域与携带 PRC1 介导的组蛋白 H2A 赖氨酸-119 单泛素化 (H2AK119Ub) 的核小体复合的冷冻电子显微镜结构。我们鉴定了 DNMT3A1 氨基末端内结合 H2AK119Ub 和核小体酸性补丁的区域。这种双齿相互作用是 DNMT3A1 与细胞中 H2AK119Ub 修饰的染色质有效结合所必需的。此外，DNMT3A1 向 Polycomb 靶基因的异常重新分布重现了癌症相关 DNA 高甲基化特征，并在细胞分化过程中抑制其转录激活。通过破坏 DNMT3A1-酸性贴片相互作用可以挽救这种效应。总之，我们的分析揭示了一个对于介导启动子 CpG 岛 DNA 高甲基化（癌症的主要分子标志）至关重要的结合界面。
During tumor development, promoter CpG islands that are normally silenced by Polycomb repressive complexes (PRCs) become DNA-hypermethylated. The molecular mechanism by which de novo DNA methyltransferase(s) [DNMT(s)] catalyze CpG methylation at PRC-regulated regions remains unclear. Here, we report a cryo-electron microscopy structure of the DNMT3A long isoform (DNMT3A1) amino-terminal region in complex with a nucleosome carrying PRC1-mediated histone H2A lysine-119 monoubiquitination (H2AK119Ub). We identify regions within the DNMT3A1 amino terminus that bind H2AK119Ub and the nucleosome acidic patch. This bidentate interaction is required for effective DNMT3A1 engagement with H2AK119Ub-modified chromatin in cells. Further, aberrant redistribution of DNMT3A1 to Polycomb target genes recapitulates the cancer-associated DNA hypermethylation signature and inhibits their transcriptional activation during cell differentiation. This effect is rescued by disruption of the DNMT3A1-acidic patch interaction. Together, our analyses reveal a binding interface critical for mediating promoter CpG island DNA hypermethylation, a major molecular hallmark of cancer.