DMAP1

更新于：2025-05-07

基本信息

别名

DMAP1、DNA methyltransferase 1 associated protein 1、DNA methyltransferase 1-associated protein 1

+ [8]

简介

Involved in transcription repression and activation. Its interaction with HDAC2 may provide a mechanism for histone deacetylation in heterochromatin following replication of DNA at late firing origins. Can also repress transcription independently of histone deacetylase activity. May specifically potentiate DAXX-mediated repression of glucocorticoid receptor-dependent transcription. Component of the NuA4 histone acetyltransferase (HAT) complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair. NuA4 may also play a direct role in DNA repair when recruited to sites of DNA damage. Participates in the nuclear localization of URI1 and increases its transcriptional corepressor activity.

关联

100 项与 DMAP1 相关的临床结果

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100 项与 DMAP1 相关的转化医学

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0 项与 DMAP1 相关的专利（医药）

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项与 DMAP1 相关的文献（医药）

2025-05-24·Journal of Biomolecular Structure and Dynamics

Identification, characterization, and CADD analysis of Plasmodium DMAP1 reveals it as a potential molecular target for new anti-malarial discovery

Article

作者: Lawrence, Merlyne ; Gupta, Ashish ; Khurana, Juhi

Developing drug resistance in the malaria parasite is a reason for apprehension compelling the scientific community to focus on identifying new molecular targets that can be exploited for developing new anti-malarial compounds. Despite the availability of the Plasmodium genome, many protein-coding genes in Plasmodium are still not characterized or very less information is available about their functions. DMAP1 protein is known to be essential for growth and plays an important role in maintaining genomic integrity and transcriptional repression in vertebrate organisms. In this study, we have identified a homolog of DMAP1 in P. falciparum. Our sequence and structural analysis showed that although PfDMAP1 possesses a conserved SANT domain, parasite protein displays significant structural dissimilarities from human homolog at full-length protein level as well as within its SANT domain. PPIN analysis of PfDMAP1 revealed it to be vital for parasite and virtual High-throughput screening of various pharmacophore libraries using BIOVIA platform-identified compounds that pass ADMET profiling and showed specific binding with PfDMAP1. Based on MD simulations and protein-ligand interaction studies two best hits were identified that could be novel potent inhibitors of PfDMAP1 protein.

2025-05-01·Journal of Affective Disorders

Chronic inflammation response as a key factor in polycystic ovary syndrome among patients with bipolar disorder

Article

作者: Huang, Jing ; Tan, Yan ; Wu, Haishan ; Teng, Ziwei ; Chen, Gong ; Chen, Zhuohui ; Chen, Jindong ; Chen, Haiyu ; Liu, Minghui ; Liu, Jieyu ; Qin, Yue

BACKGROUNDThis study aimed to investigate serum inflammatory factor levels of polycystic ovary syndrome (PCOS) in female patients with bipolar disorder (BD) to explore the related inflammatory molecular mechanisms preliminarily.METHODSThe study recruited 72 female drug-naïve patients with BD and 98 female healthy controls (HCs). Demographic information, menstrual cycles, sex hormone levels, and ovarian ultrasound data were collected from them. Additionally, their serum inflammatory factor levels and the proteomics of peripheral blood mononuclear cells were analyzed.RESULTSThe levels of interleukin (IL)-8 and IL-13 were significantly higher in patients with BD than in HCs (p < 0.05), and the IL-8 level was higher in BD patients with PCOS than in those without (adjusted p = 0.07). Bioinformatics analysis revealed that downregulated genes with significant differences between the two groups were all involved in immune-inflammatory-related pathways, and the expression of downregulated genes BTN3A2, MAP2K5, JCHAIN-B, and DMAP1 showed substantial differences and consistent trends between the two groups.CONCLUSIONIL-8-related chronic inflammatory response is closely associated with PCOS in BD patients, and genes such as BTN3A2 may mediate this chronic inflammatory response by negatively regulating the abnormal differentiation of T helper 17 cells, serving as one of the mechanisms underlying its pathogenesis.

2025-03-01·Gene

Incidence of alternative splicing associated with sex and opioid effects in the axon guidance pathway

Article

作者: Sunderland, Gloria R ; Bhamidi, Sreelaya ; Gomez, Andrea N ; Southey, Bruce R ; Rodriguez-Zas, Sandra L

The alternative splicing of a gene results in distinct transcript isoforms that can result in proteins that differ in function. Alternative splicing processes are prevalent in the brain, have varying incidence across brain regions, and can present sexual dimorphism. Exposure to opiates and other substances of abuse can also alter the type and incidence of the splicing process and the relative abundance of the isoforms produced. The disruption of alternative splicing patterns associated with sex differences and morphine exposure in the prefrontal cortex of a pig model was studied. The numbers of genes presenting one or more significant (FDR-adjusted p-value < 0.05) alternative splicing events were 933 and 1,368 genes when comparing females relative to males and morphine- relative to saline-treated animals, respectively. The sex-dependent opioid effect was most extreme in the contrast between morphine- versus saline-treated males with 1,934 significantly differentially spliced genes. The most frequent and significant alternative splicing type was skipped exon (∼56 % event), followed by retained intron (∼15 % events). The pathways encompassing a significant number of differentially spliced genes included axon guidance, glutamatergic synapses, circadian rhythm, and lysine degradation. Genes in these pathways included ROBO1, SEMA6C, GRIN3A, GRM2, ARNTL, CLOCK, HYKK, and DOT1L. Transcription factors ETV7 and DMAP1 presented a significant number of differentially spliced target genes. The distribution of the genes presenting differential alternative splicing in the axon guidance and circadian rhythm pathways indicates that this regulatory mechanism impacts hubs and peripheral genes. The identification of sexual dimorphism in the effect of morphine across multiple pathways confirms the necessity to explore the effects of drugs of abuse within sex. Altogether, our findings advance the understanding of the response to factors that can impact the activity of excitatory synapses by modulating transcriptional mechanisms that support the plasticity of the prefrontal cortex.

项与 DMAP1 相关的新闻（医药）

2024-08-24

·生物探索

Nat Commun丨徐彦辉团队报道人源TIP60复合物的组装机制及其结合核小体的模型

引言在真核细胞中，核小体是染色质的基本组成单元，其可以通过改变自身的定位、共价修饰组蛋白及置换组蛋白变体的方式来改变染色质的结构和调控基因表达。核小体的这些调控主要由染色质重塑复合物和组蛋白修饰复合物来执行。人源TIP60复合物（hTIP60）是一个具有 17 个亚基的超大型复合物（分子量约为1.7 MDa），它的独特之处在于同时拥有组蛋白变体置换和组蛋白乙酰化活性。根据酶活和分子组成上的相似性，hTIP60被认为是酵母中 SWR-C复合物（ySWR-C）和 NuA4复合物（yNuA4）的融合物。之前的研究表明，hTIP60在多种生物学过程中发挥重要作用，包括转录调控、DNA修复、细胞周期控制和胚胎发育等，同时hTIP60的突变被认为与多种癌症相关。过往的研究报道了hTIP60 复合物的同源物如 ySWR-C、 yNuA4、hSRCAP-C等复合物的高分辨冷冻电镜结构，从结构生物学的角度阐明了这些复合物结合底物核小体并发挥活性的机制，另外也有一些研究通过晶体学、核磁共振波谱（NMR）等技术对 hTIP60 复合物的部分亚基如YL1、YEATS4、MRG15-MRGBP、EPC1-MBTD1等进行了结构分析，而hTIP60 复合物的完整结构信息一直处于空白状态，因此目前该复合物的组装及其结合核小体的模式仍然很不清楚。 2024年8月17日，复旦大学徐彦辉团队在Nature Communications杂志上在线发表了题为Structure of the human TIP60 complex的研究论文。该研究利用单颗粒冷冻电镜技术，结合交联质谱及体外生化功能分析阐明了hTIP60复合物精细的分子组装机制，并提出了该复合物作用于核小体的模型。根据已有的关于hTIP60复合物的报道及其与yNuA4和ySWR-C复合物的同源性研究，由17个亚基组成的hTIP60复合物可被划分为5个模块，其分别为含有Snf2家族ATPase结构域的motor 模块、调节性的ARP模块、发挥乙酰化功能的HAT模块、含有多个组蛋白修饰阅读器的TINTIN（Trimer Independent of NuA4 for Transcription Interactions with Nucleosomes）模块、以及用于结合转录激活因子的TRRAP模块（图1）。图1. 人源TIP60复合物的模块化组织和结构域示意图(Credit: Nature Communications) 徐彦辉课题组的这项工作报道了hTIP60复合物单体状态下的冷冻电镜结构，9.4 Å的整体冷冻电镜密度图表明该复合物主要由两大部分构成，这两部分被称为核心亚复合物（包括motor 模块及ARP模块）和 TRRAP模块，它们通过一段柔性区域连接（图1a），随后研究人员将这两部分的分辨率均细化至3.2 Å（图1b）。这些结构表明EP400亚基作为hTIP60复合物的骨架蛋白，整合了复合物的motor 模块、ARP（actin-related protein）模块和TRRAP 模块。在motor模块中，RUVBL1-RUVBL2六聚体是EP400亚基的ATPase结构域和YL1亚基组装的刚性核心。在ARP模块中，ACTL6A-ACTB异二聚体和一个额外的ACTL6A 亚基通过疏水作用与EP400 亚基的HSA螺旋进行接触；而亚基 DMAP1、EPC1和EP400之间的相互作用网络增强了ACTL6A-ACTB异二聚体和EP400-HSA之间的结合。在TRRAP模块中，EP400亚基的 SANT结构域及其C端区域与TRRAP亚基存在广泛的相互作用界面。总体来看，ARP模块与motor模块之间的连接非常稳定，而其与TRRAP模块之间的连接非常灵活，这是hTIP60复合物特有的结构特征。除了上述已经确定的模块外，hTIP60 复合物的整体冷冻电镜密度图中TRRAP模块和核心亚复合物之间还存在了一些较弱的密度，这些密度可能属于hTIP60复合物其他的模块，包括HAT模块和TINTIN模块（图2a）。因此在hTIP60复合物中，其HAT模块、TINTIN模块和TRRAP模块都以灵活的方式连接到核心亚复合物中，这种结构上的可塑性可能有助于该复合物在细胞中识别复杂的染色质环境并找到合适的底物。图2. 人源TIP60复合物单体的结构：(a). hTIP60 复合物在低轮廓水平（low contour level，左）和高轮廓水平（high contour level，右）的整体冷冻电镜密度图。(b). 人源TIP60复合物单体状态下的冷冻电镜重构密度图及三维模型。(Credit: Nature Communications) 此外，该研究还报道了与核小体结合的hTIP60复合物的较低分辩率的冷冻电镜结构，该结构显示核小体结合在hTIP60复合物的核心亚复合物和TRRAP模块之间（图3），值得注意的是，在对hTIP60-核小体复合物的冷冻电镜数据进行仔细的分析后，研究人员并未观察到hTIP60的核心亚复合物像其他重塑复合物那样（即催化亚基的ATPase结构域抓住核小体的DNA以进行染色质重塑）结合核小体的构象。图3. 核小体结合状态下的人源TIP60复合物的冷冻电镜重构密度图及模型(Credit: Nature Communications) 综上所述，该研究揭示了hTIP60 复合物的 motor 模块、ARP 模块和 TRRAP 模块高分辨的结构信息，阐明了该复合物的分子组装机制及各模块之间的相互作用模式；并首次报道了和核小体结合的hTIP60复合物的冷冻电镜重构密度图，从结构生物学的角度对该复合物如何与核小体作用提供了见解，为继续探索hTip60复合物作用于染色质并调控基因表达的机制提供了线索。参考文献 https://www.nature.com/articles/s41467-024-51259-z 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

2024-02-13

·生物探索

Cell Discov | 冷冻电镜揭示的SRCAP复合体与核小体结合的高分辨率结构

引言组蛋白变体H2A.Z在启动子上发现并调节转录。ATP依赖性染色质重塑器SRCAP复合体(SRCAP-C)促进标准组蛋白H2A.Z-H2B二聚体被H2A–H2B取代。2024年2月8日，复旦大学徐彦辉及Wang Li共同通讯在Cell Discovery（IF 33.5）在线发表题为“Structural insights into histone exchange by human SRCAP complex”的研究论文，该研究确定了人类SRCAP-C与含H2A的核小体结合的结构。在真核细胞中，基因组DNA包裹在组蛋白八聚体周围，在基因组上产生排列的核小体。典型核小体包含四个组蛋白H2A、H2B、H3和H4的两个拷贝。为了实现功能调节，ATP依赖性染色质重塑复合体(重塑复合体)改变核小体的组成和沿DNA的位置。染色质重塑复合物根据其催化ATP酶的异同可分为4个家族：模仿开关(ISWI)、染色质结构域解旋酶DNA结合(CHD)、开关/sucrose不可发酵(SWI/ SNF)和肌醇营养不良80 (INO80)。其中两种重塑蛋白由单个亚基(CHD家族)或几个亚基(ISWI家族)组成。相比之下，SWI/SNF和INO80家族是多亚基复合物，除了超家族II解旋酶样运动亚基外，还含有肌动蛋白和肌动蛋白相关蛋白(ARPs)以及其他具有不同功能的重塑蛋白特异性亚基。人类染色质重塑子SNF2相关CPB激活蛋白(SRCAP)复合物(SRCAP-C)及其酵母对应物SWR1复合物(SWR-C)属于INO80染色质重塑子家族。SRCAP-C和SWR-C可以用H2A.Z-H2B二聚体以ATP依赖的方式取代H2A-H2B二聚体，这一过程可能需要组蛋白伴侣。生成的H2A.Z含核小体富集于几乎所有常染色质基因的启动子区域，并参与转录和其他过程的调控，如DNA复制、DNA修复和染色体分离。在真核细胞中，H2A.Z主要存在于它位于启动子的远端，在RNAPII的起始和延伸中起关键作用。H2A.Z在复制起点也广泛富集，并通过调节早期复制起点的起始和复制时间与DNA复制直接相关。此外，研究表明，协调H2A.Z双链断裂(DSBs)中的动力学对DNA修复至关重要。H2A.Z在染色体分离过程中也起着至关重要的作用，以维持基因组处于稳定状态。与其他染色质重塑子不同，SWR-C与核小体结合并诱导DNA展开和重新包裹，但不产生净DNA易位，表现出一种典型特征。核小体结合的SRCAP-C的整体结构（Credit: Cell Discovery）人SRCAP-C是一种~1-MDa复合物，由SRCAP、YL1、RUVBL1、RUVBL2、ARP6、ZNHIT1、DMAP1、ACTL6A、ACTB和YEATS4等10个亚基组成，酵母SRCAP-C由10个相同的亚基组成，分别为Swr1、Swc2、RvB1、RvB2、ARP6、Swc6、Swc4、Arp4、Actin、Yaf9和另外4个酵母特异性亚基Swc3、Swc5、Swc7和Bdf1。先前的研究已经揭示了酵母SWR-C、人SRCAP-C和核小体结合酵母SWR-C在ATP类似物ADP-BeFx存在下的结构。SWR-C含有RuvBL蛋白的异六聚体，Swr1中的插入物通过RuvBL六聚体延伸。Swr1的ATP酶结构域在超螺旋位置(SHL) 2上抓住DNA，导致DNA在ADP-BeFx结合状态下移位1bp。此外，进入DNA部分被解开，组蛋白核心“弯曲”。与酵母SWR-C相比，SRCAP-C采用了大致相似的结构，包含一个带有两个独立臂的环状“头”。该研究测定了核小体结合的SRCAP-C在不同核苷酸结合状态下的结构，并进行了结构引导染色质免疫沉淀测序(ChIP-seq)分析，以测试ZNHIT1对H2A.Z在体内掺入的影响。SRCAP-C介导的Z交换。SRCAP亚基集成了一个6亚基肌动蛋白相关蛋白(ARP)模块和一个含ATP酶的马达模块。ATP酶相关的ARP模块沿DNA包围核小体的一半，并可能抑制净DNA易位，这是SRCAP-C的独特特征。motor模块在载脂蛋白(无核苷酸)、ADP结合和ADP-BeFx结合状态下采用不同的核小体结合模式，表明ATP酶驱动的运动通过解开进入DNA的包裹使H2A-H2B不稳定，并通过ZNHIT1亚基将H2A-H2B拉出核小体。结构导向的染色质免疫沉淀测序分析证实了H2A接触ZNHIT1维持H2A.Z基因组上占用率的必要性。该研究为SRCAP-C介导的H2A-H2A.Z交换机制提供了结构性的见解。原文链接https://www.nature.com/articles/s41421-023-00640-1责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Science最新发布：全世界最前沿的125个科学问题热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文Nature | 癌症与神经系统的致命舞蹈

细胞疗法