• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

AF10的PZP结构域识别未修饰的H3K27以调控DOT1L介导的H3K79甲基化。

The PZP Domain of AF10 Senses Unmodified H3K27 to Regulate DOT1L-Mediated Methylation of H3K79.

作者信息

Chen Shoudeng, Yang Ze, Wilkinson Alex W, Deshpande Aniruddha J, Sidoli Simone, Krajewski Krzysztof, Strahl Brian D, Garcia Benjamin A, Armstrong Scott A, Patel Dinshaw J, Gozani Or

机构信息

Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

Department of Biology, Stanford University, Stanford, CA 94305, USA.

出版信息

Mol Cell. 2015 Oct 15;60(2):319-27. doi: 10.1016/j.molcel.2015.08.019. Epub 2015 Oct 1.

DOI:10.1016/j.molcel.2015.08.019
PMID:26439302
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4609290/
Abstract

AF10, a DOT1L cofactor, is required for H3K79 methylation and cooperates with DOT1L in leukemogenesis. However, the molecular mechanism by which AF10 regulates DOT1L-mediated H3K79 methylation is not clear. Here we report that AF10 contains a "reader" domain that couples unmodified H3K27 recognition to H3K79 methylation. An AF10 region consisting of a PHD finger-Zn knuckle-PHD finger (PZP) folds into a single module that recognizes amino acids 22-27 of H3, and this interaction is abrogated by H3K27 modification. Structural studies reveal that H3 binding triggers rearrangement of the PZP module to form an H3(22-27)-accommodating channel and that the unmodified H3K27 side chain is encased in a compact hydrogen-bond acceptor-lined cage. In cells, PZP recognition of H3 is required for H3K79 dimethylation, expression of DOT1L-target genes, and proliferation of DOT1L-addicted leukemic cells. Together, our results uncover a pivotal role for H3K27-via readout by the AF10 PZP domain-in regulating the cancer-associated enzyme DOT1L.

摘要

AF10是一种DOT1L辅因子，是H3K79甲基化所必需的，并在白血病发生过程中与DOT1L协同作用。然而，AF10调节DOT1L介导的H3K79甲基化的分子机制尚不清楚。在此，我们报告AF10包含一个“读取器”结构域，该结构域将未修饰的H3K27识别与H3K79甲基化偶联起来。由一个PHD指-Zn指节-PHD指（PZP）组成的AF10区域折叠成一个单一模块，该模块识别H3的第22-27位氨基酸，并且这种相互作用会被H3K27修饰所消除。结构研究表明，H3结合触发PZP模块重排以形成容纳H3(22-27)的通道，并且未修饰的H3K27侧链被包裹在一个由紧密排列的氢键受体构成的笼状结构中。在细胞中，PZP对H3的识别是H3K79二甲基化、DOT1L靶基因表达以及对DOT1L成瘾的白血病细胞增殖所必需的。总之，我们的结果揭示了H3K27通过AF10 PZP结构域的读出在调节癌症相关酶DOT1L中起关键作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7bf6/4609290/5d308a5f1c83/nihms719027f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7bf6/4609290/d312da2fc79c/nihms719027f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7bf6/4609290/144d1e32d685/nihms719027f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7bf6/4609290/27928781a6d9/nihms719027f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7bf6/4609290/5d308a5f1c83/nihms719027f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7bf6/4609290/d312da2fc79c/nihms719027f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7bf6/4609290/144d1e32d685/nihms719027f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7bf6/4609290/27928781a6d9/nihms719027f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7bf6/4609290/5d308a5f1c83/nihms719027f4.jpg

相似文献

1
The PZP Domain of AF10 Senses Unmodified H3K27 to Regulate DOT1L-Mediated Methylation of H3K79.AF10的PZP结构域识别未修饰的H3K27以调控DOT1L介导的H3K79甲基化。
Mol Cell. 2015 Oct 15;60(2):319-27. doi: 10.1016/j.molcel.2015.08.019. Epub 2015 Oct 1.
2
AF10 (MLLT10) prevents somatic cell reprogramming through regulation of DOT1L-mediated H3K79 methylation.AF10（MLLT10）通过调控 DOT1L 介导的 H3K79 甲基化来阻止体细胞重编程。
Epigenetics Chromatin. 2021 Jul 2;14(1):32. doi: 10.1186/s13072-021-00406-7.
3
DOT1L interaction partner AF10 controls patterning of H3K79 methylation and RNA polymerase II to maintain cell identity.DOT1L 相互作用伙伴 AF10 控制 H3K79 甲基化和 RNA 聚合酶 II 的模式，以维持细胞的身份。
Stem Cell Reports. 2023 Dec 12;18(12):2451-2463. doi: 10.1016/j.stemcr.2023.10.017. Epub 2023 Nov 22.
4
DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells.在哺乳动物细胞中，DOT1L/KMT4的募集和H3K79甲基化与基因转录普遍相关。
Mol Cell Biol. 2008 Apr;28(8):2825-39. doi: 10.1128/MCB.02076-07. Epub 2008 Feb 19.
5
Deficiency of H3K79 histone methyltransferase Dot1-like protein (DOT1L) inhibits cell proliferation.H3K79 组蛋白甲基转移酶 Dot1 样蛋白（DOT1L）缺乏可抑制细胞增殖。
J Biol Chem. 2012 Feb 17;287(8):5588-99. doi: 10.1074/jbc.M111.328138. Epub 2011 Dec 21.
6
Global reduction of the epigenetic H3K79 methylation mark and increased chromosomal instability in CALM-AF10-positive leukemias.CALM-AF10阳性白血病中表观遗传H3K79甲基化标记的整体减少及染色体不稳定性增加。
Blood. 2009 Jul 16;114(3):651-8. doi: 10.1182/blood-2009-03-209395. Epub 2009 May 14.
7
AF9 YEATS domain links histone acetylation to DOT1L-mediated H3K79 methylation.AF9 YEATS结构域将组蛋白乙酰化与DOT1L介导的H3K79甲基化联系起来。
Cell. 2014 Oct 23;159(3):558-71. doi: 10.1016/j.cell.2014.09.049.
8
The histone methyltransferase Dot1/DOT1L as a critical regulator of the cell cycle.组蛋白甲基转移酶Dot1/DOT1L作为细胞周期的关键调节因子。
Cell Cycle. 2014;13(5):726-38. doi: 10.4161/cc.28104. Epub 2014 Feb 6.
9
A higher-order configuration of the heterodimeric DOT1L-AF10 coiled-coil domains potentiates their leukemogenenic activity.同源二聚体 DOT1L-AF10 卷曲螺旋结构域的高级别构象增强了它们的致白血病活性。
Proc Natl Acad Sci U S A. 2019 Oct 1;116(40):19917-19923. doi: 10.1073/pnas.1904672116. Epub 2019 Sep 16.
10
DOT1L-mediated H3K79 methylation in chromatin is dispensable for Wnt pathway-specific and other intestinal epithelial functions.组蛋白 H3K79 甲基化酶 DOT1L 在染色质中的作用对于 Wnt 通路特异性和其他肠道上皮功能并非必需。
Mol Cell Biol. 2013 May;33(9):1735-45. doi: 10.1128/MCB.01463-12. Epub 2013 Feb 19.

引用本文的文献

1
Genetic Insights into Brain Morphology: a Genome-Wide Association Study of Cortical Thickness and T-Weighted MRI Gray Matter-White Matter Intensity Contrast.大脑形态学的遗传学见解：一项关于皮质厚度和T加权磁共振成像灰质-白质强度对比度的全基因组关联研究。
Neuroinformatics. 2025 Apr 1;23(2):26. doi: 10.1007/s12021-025-09722-9.
2
Targeting chromatin modifying complexes in acute myeloid leukemia.靶向急性髓系白血病中的染色质修饰复合物
Stem Cells Transl Med. 2025 Feb 11;14(2). doi: 10.1093/stcltm/szae089.
3
Histone H3.3 lysine 9 and 27 control repressive chromatin at cryptic enhancers and bivalent promoters.

本文引用的文献

1
Mixed lineage rearranged leukaemia: pathogenesis and targeting DOT1L.混合谱系重排白血病：发病机制与靶向DOT1L
Curr Opin Hematol. 2015 Mar;22(2):92-6. doi: 10.1097/MOH.0000000000000123.
2
AF10 regulates progressive H3K79 methylation and HOX gene expression in diverse AML subtypes.AF10 调节不同 AML 亚型中 H3K79 的渐进性甲基化和 HOX 基因表达。
Cancer Cell. 2014 Dec 8;26(6):896-908. doi: 10.1016/j.ccell.2014.10.009. Epub 2014 Nov 20.
3
AF9 YEATS domain links histone acetylation to DOT1L-mediated H3K79 methylation.AF9 YEATS结构域将组蛋白乙酰化与DOT1L介导的H3K79甲基化联系起来。
组蛋白 H3.3 赖氨酸 9 和 27 控制隐蔽增强子和二价启动子处的抑制性染色质。
Nat Commun. 2024 Aug 30;15(1):7557. doi: 10.1038/s41467-024-51785-w.
4
An emerging maestro of immune regulation: how DOT1L orchestrates the harmonies of the immune system.免疫调节领域的新兴大师：DOT1L 如何协调整个免疫系统的和谐运作。
Front Immunol. 2024 Jun 19;15:1385319. doi: 10.3389/fimmu.2024.1385319. eCollection 2024.
5
Defining the heterogeneous molecular landscape of lung cancer cell responses to epigenetic inhibition.定义肺癌细胞对表观遗传抑制反应的异质性分子格局。
bioRxiv. 2024 Sep 24:2024.05.23.592075. doi: 10.1101/2024.05.23.592075.
6
Guiding the HBO1 complex function through the JADE subunit.通过JADE亚基引导HBO1复合物的功能。
Nat Struct Mol Biol. 2024 Jul;31(7):1039-1049. doi: 10.1038/s41594-024-01245-2. Epub 2024 Mar 6.
7
Signature construction and molecular subtype identification based on liver-specific genes for prediction of prognosis, immune activity, and anti-cancer drug sensitivity in hepatocellular carcinoma.基于肝癌中肝脏特异性基因的特征构建及分子亚型鉴定以预测预后、免疫活性和抗癌药物敏感性
Cancer Cell Int. 2024 Feb 19;24(1):78. doi: 10.1186/s12935-024-03242-3.
8
DOT1L interaction partner AF10 controls patterning of H3K79 methylation and RNA polymerase II to maintain cell identity.DOT1L 相互作用伙伴 AF10 控制 H3K79 甲基化和 RNA 聚合酶 II 的模式，以维持细胞的身份。
Stem Cell Reports. 2023 Dec 12;18(12):2451-2463. doi: 10.1016/j.stemcr.2023.10.017. Epub 2023 Nov 22.
9
KDM4 Demethylases: Structure, Function, and Inhibitors.KDM4去甲基化酶：结构、功能及抑制剂
Adv Exp Med Biol. 2023;1433:87-111. doi: 10.1007/978-3-031-38176-8_5.
10
CRISPR-ChIP reveals selective regulation of H3K79me2 by Menin in MLL leukemia.CRISPR-ChIP 揭示 Menin 对 MLL 白血病中 H3K79me2 的选择性调控。
Nat Struct Mol Biol. 2023 Oct;30(10):1592-1606. doi: 10.1038/s41594-023-01087-4. Epub 2023 Sep 7.
Cell. 2014 Oct 23;159(3):558-71. doi: 10.1016/j.cell.2014.09.049.
4
Role of PRC2-associated factors in stem cells and disease.PRC2相关因子在干细胞和疾病中的作用。
FEBS J. 2015 May;282(9):1723-35. doi: 10.1111/febs.13083. Epub 2014 Oct 25.
5
The emerging roles of DOT1L in leukemia and normal development.DOT1L 在白血病和正常发育中的新兴作用。
Leukemia. 2014 Nov;28(11):2131-8. doi: 10.1038/leu.2014.169. Epub 2014 May 23.
6
Polycomb-dependent H3K27me1 and H3K27me2 regulate active transcription and enhancer fidelity.多梳依赖的 H3K27me1 和 H3K27me2 调节活性转录和增强子保真度。
Mol Cell. 2014 Jan 9;53(1):49-62. doi: 10.1016/j.molcel.2013.10.030. Epub 2013 Nov 27.
7
Crosstalk between epigenetic readers regulates the MOZ/MORF HAT complexes.表观遗传阅读蛋白之间的相互作用调控MOZ/MORF组蛋白乙酰转移酶复合体。
Epigenetics. 2014 Feb;9(2):186-93. doi: 10.4161/epi.26792. Epub 2013 Oct 29.
8
Exchange of associated factors directs a switch in HBO1 acetyltransferase histone tail specificity.相关因素的交换指导 HBO1 乙酰转移酶组蛋白尾部特异性的转变。
Genes Dev. 2013 Sep 15;27(18):2009-24. doi: 10.1101/gad.223396.113.
9
Potent inhibition of DOT1L as treatment of MLL-fusion leukemia.强效抑制 DOT1L 治疗 MLL 融合白血病。
Blood. 2013 Aug 8;122(6):1017-25. doi: 10.1182/blood-2013-04-497644. Epub 2013 Jun 25.
10
Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma.功能获得性 H3 突变抑制 PRC2 活性，该突变存在于小儿脑胶质瘤中。
Science. 2013 May 17;340(6134):857-61. doi: 10.1126/science.1232245. Epub 2013 Mar 28.