更新于：2024-11-01

APOBEC3B

更新于：2024-11-01

基本信息

别名

A3B、APOBEC3B、apolipoprotein B mRNA editing enzyme catalytic subunit 3B

+ [5]

简介

DNA deaminase (cytidine deaminase) which acts as an inhibitor of retrovirus replication and retrotransposon mobility via deaminase-dependent and -independent mechanisms. After the penetration of retroviral nucleocapsids into target cells of infection and the initiation of reverse transcription, it can induce the conversion of cytosine to uracil in the minus-sense single-strand viral DNA, leading to G-to-A hypermutations in the subsequent plus-strand viral DNA. The resultant detrimental levels of mutations in the proviral genome, along with a deamination-independent mechanism that works prior to the proviral integration, together exert efficient antiretroviral effects in infected target cells. Selectively targets single-stranded DNA and does not deaminate double-stranded DNA or single- or double-stranded RNA. Exhibits antiviral activity against simian immunodeficiency virus (SIV), hepatitis B virus (HBV) and human T-cell leukemia virus type 1 (HTLV-1) and may inhibit the mobility of LTR and non-LTR retrotransposons.

关联

项与 APOBEC3B 相关的药物

WO2022159715

专利挖掘

靶点

APOBEC3B

作用机制-

在研机构

Genome Research Ltd. [+1]

原研机构

The Broad Institute, Inc. [+3]

在研适应症

肿瘤

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

WO2024042231

专利挖掘

靶点

APOBEC3B

作用机制-

在研机构

Facultés Universitaires Notre-Dame de la Paix

原研机构

Facultés Universitaires Notre-Dame de la Paix

在研适应症

肿瘤

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 APOBEC3B 相关的临床结果

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100 项与 APOBEC3B 相关的转化医学

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0 项与 APOBEC3B 相关的专利（医药）

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357

项与 APOBEC3B 相关的文献（医药）

2024-12-01·Molecular Therapy: Oncology

APOBEC3B expression in 293T viral producer cells drives mutations in chimeric antigen receptors and reduces CAR T cell efficacy

Article

作者: Liseth, Olivia ; Kendall, Benjamin ; Tonne, Jason ; Vile, Richard ; Sangsuwannukul, Thanich ; Swanson, Jack ; Metko, Muriel ; Thompson, Jill

Chimeric antigen receptor (CAR) T cells are a clinically approved therapy for blood cancers. To produce clinical-grade CAR T cells, a retroviral or lentiviral vector is used to deliver the CAR and associated genes to patient T cells. Apolipoprotein B editing enzyme, catalytic polypeptide 3 (APOBEC3) enzymes are known to be upregulated after transfection and retroviral infection and to deaminate cytidine to uracil in nucleic acids, resulting in cytidine-to-thymine mutations in DNA. Here, we hypothesized that APOBEC3 enzymes, induced during the production of CAR T cells, impact the efficacy of the resulting CAR T cells. We demonstrated that APOBEC3 family member APOBEC3B was upregulated at the RNA and protein levels after transfection of HEK293T cells with plasmids to make lentivirus, and that APOBEC3 signature mutations were present in the CAR construct. APOBEC3B overexpression in HEK293T cells led to further mutations in the resulting CAR T cells, and significantly decreased CAR T cell killing. APOBEC3B knockout in HEK293T cells led to reduced mutations in the CAR construct and significantly increased in CAR T cell killing. These results suggest that generation of CAR-expressing viruses from producer cell lines deficient in genome-modifying proteins such as APOBEC3B could enhance the quality of CAR T cell production.

2024-11-01·Reproductive BioMedicine Online

Genetic alteration of mRNA editing enzyme APOBEC3B in the pathogenesis of ovarian endometriosis

Article

作者: Gopal, Gopisetty ; Rayala, Suresh Kumar ; Gopisetty, Gopal ; Balunathan, Nandhini ; Srinivasan, Bhuvana ; Venkatraman, Ganesh ; Joseph, Leena Dennis ; Balamurugan, Srikanth Swamy Swaroop ; Saravanan, Roshni ; Rajendran, Swetha ; Swaroop B, Srikanth Swamy ; Shanmugasundaram, Gouthaman ; Dev, Bhawna ; Ganesan, Kumaresan ; Balasubramanian, Vaishnavi

RESEARCH QUESTIONWhat are the specific genetic alterations and associated network in endometriotic cells responsible for the disease pathogenesis?DESIGNCase control experimental study involving 45 women with endometriosis who underwent laparoscopic surgery (case) and 45 normal samples from women undergoing total abdominal hysterectomy (control). The endometrial samples were subjected to whole exome sequencing (WES) of endometriotic tissue and copy number variation analysis. Validation of gene hits were obtained from WES using polymerase chain reaction techniques, immunological techniques, in-silico tools and transgenic cell line models.RESULTSGermline heterozygous deletion of mRNA editing enzyme subunit APOBEC3B was identified in about 96% of endometriosis samples. The presence of germline deletion was confirmed with blood, endometrium and normal ovary samples obtained from the same patient. APOBEC3B deletions resulted in a hybrid protein that activates A1CF. APOBEC3B deletion can be a major cause of changes in the endometriotic microenvironment, and contributes to the pathogenesis and manifestation of the disease. The effect of APOBEC3B deletion was proved by in-vitro experiments in a cell line model, which displayed endometriosis-like characteristics. APOBEC3B germline deletion plays a major role in the pathogenesis of endometriosis, which is evident by the activation of A1CF, an increase in epithelial to mesenchymal transition, cellular proliferation, inflammation markers and a decrease in apoptosis markers.CONCLUSIONThe deleterious effects caused by APOBEC3B deletion in endometriosis were identified and confirmed. These results might provide a base for identifying the complete pathogenetic mechanism of endometriosis, thereby moving a step closer to better diagnosis and treatment options.

2024-08-07·GENETICS

The cytidine deaminase APOBEC3C has unique sequence and genome feature preferences

Article

作者: Brown, Grant W

AbstractAPOBEC proteins are cytidine deaminases that restrict the replication of viruses and transposable elements. Several members of the APOBEC3 family, APOBEC3A, APOBEC3B, and APOBEC3H-I, can access the nucleus and cause what is thought to be indiscriminate deamination of the genome, resulting in mutagenesis and genome instability. Although APOBEC3C is also present in the nucleus, the full scope of its deamination target preferences is unknown. By expressing human APOBEC3C in a yeast model system, I have defined the APOBEC3C mutation signature, as well as the preferred genome features of APOBEC3C targets. The APOBEC3C mutation signature is distinct from those of the known cancer genome mutators APOBEC3A and APOBEC3B. APOBEC3C produces DNA strand-coordinated mutation clusters, and APOBEC3C mutations are enriched near the transcription start sites of active genes. Surprisingly, APOBEC3C lacks the bias for the lagging strand of DNA replication that is seen for APOBEC3A and APOBEC3B. The unique preferences of APOBEC3C constitute a mutation profile that will be useful in defining sites of APOBEC3C mutagenesis in human genomes.

项与 APOBEC3B 相关的新闻（医药）

2024-03-19

·Science Daily

Role of key enzymes that drive cancer mutations discovered

A research team has discovered the key role that the APOBEC3A and APOBEC3B enzymes play in driving cancer mutations by modifying the DNA in tumor genomes, offering potential new targets for intervention strategies. A research team led by the University of California, Irvine has discovered the key role that the APOBEC3A and APOBEC3B enzymes play in driving cancer mutations by modifying the DNA in tumor genomes, offering potential new targets for intervention strategies. The study, published today online in the journal Nature Communications, describes how the researchers identified the process by which APOBEC3A and APOBEC3B detect specific DNA structures, resulting in mutations at distinct positions within the tumor genome. "It's critical to understand how cancer cells accumulate mutations leading to hot spots that contribute to disease progression, drug resistance and metastasis," said corresponding author Rémi Buisson, UCI assistant professor of biological chemistry. "Both APOBEC3A and APOBEC3B were known to generate mutations in many kinds of tumors, but until now we did not know how to identify the specific type caused by each. This finding will allow us to develop novel therapies to suppress mutation formation by directly targeting each enzyme accordingly." In this study, graduate student Ambrocio Sanchez and postdoctoral fellow Pedro Ortega, both in Buisson's laboratory at the UCI School of Medicine, developed a new method to characterize the particular kind of DNA modified by APOBEC3A and APOBEC3B. It revealed that the two enzymes do not recognize the same DNA sequences and structures within the genomes of cancer cells. Based on this observation, an innovative approach utilizing these unique target preferences was employed to classify cancer patients who had accumulated mutations caused by each enzyme. "The next steps are to investigate whether mutations caused by these enzymes lead to various types of therapy resistance. It's also critical to identify molecules that inhibit APOBEC3A and APOBEC3B to prevent mutations from forming. Our findings could, in the future, help to assess patient risk before treatment and suppress tumor evolution using the appropriate drug therapy," Buisson said. Other team members included undergraduate and graduate students and postdoctoral fellows from UCI, Harvard Medical School, the University of Southern California, the University of Texas at San Antonio and the University of Minnesota. This work was supported by the National Institutes of Health's Research Supplements to Promote Diversity in Health-Related Research program under award R37-CA252081-S; California Institute for Regenerative Medicine stem cell biology training grant TG2-01152; European Molecular Biology Organization postdoctoral fellowship ALTF 213-2023; Cancer Prevention and Research Institute of Texas research training award RP 170345 and Recruitment of Established Investigators award CPRIT RR220053; the National Cancer Institute under awards R37-VA252081 and P01-CA234228; the National Institute of Allergy and Infectious Diseases under award R01 AI150524; and access to UCI's Genomics Research and Technology Hub, affiliated with the Chao Family Comprehensive Cancer Center, under grant P30-CA062203.

2023-07-23

·生物探索

前列腺癌雄激素受体靶向治疗耐药的潜在机制

肿瘤的突变负担和异质性已被认为是对许多靶向治疗产生耐药性的原因。胞嘧啶脱氨酶APOBEC蛋白与超过70%的人类癌症的突变特征有关。然而，癌细胞如何劫持APOBEC介导的突变机制以促进肿瘤异质性，从而促进治疗耐药性的机制尚不清楚。2023年7月20日，德克萨斯大学西南医学中心牟平团队在Cancer Cell 在线发表题为“Loss of SYNCRIP unleashes APOBEC-driven mutagenesis, tumor heterogeneity, and AR-targeted therapy resistance in prostate cancer”的研究论文，该研究发现SYNCRIP是一种内源性分子制动器，可以抑制前列腺癌(PCa)中APOBEC驱动的突变。在SYNCRIP缺失的PCa细胞中，过度激活的APOBEC3B是一个关键的突变子，代表了PCa中一些常见突变基因(包括FOXA1、EP300)驱动突变的分子来源。功能筛选确定了APOBEC3B突变的PCa中雄激素受体(AR)靶向治疗耐药的8个关键驱动因素：BRD7、CBX8、EP300、FOXA1、HDAC5、HSF4、STAT3和AR。这些结果揭示了APOBEC驱动的突变释放的细胞内在机制，该机制在赋予PCa AR靶向治疗耐药中起重要作用。针对驱动癌基因的治疗方法的发展已经彻底改变了许多癌症的临床管理；然而，它们的反应的幅度和持续时间仍然是可变的，并且不可避免地发生抵抗。大量证据表明，突变负担的增加和遗传异质性既是抗性的燃料，也是抗性的来源。因此，阐明这种增加的诱变和遗传异质性的分子起源和机制对于培养下一代抗癌疗法和克服耐药性至关重要。遗传异质性可能源于许多癌症的基因组不稳定性。新出现的数据表明，肿瘤细胞可以劫持稳态调节机制，从而加强突变，作为促进基因组不稳定的可能途径。这种机制的一个重要例子是脱氨酶APOBEC蛋白。在超过70%的人类癌症中观察到APOBEC驱动的突变模式增加。然而，癌细胞如何劫持APOBEC介导的突变机制以促进肿瘤异质性，从而促进治疗耐药性的机制在很大程度上仍然未知。机理模式图（图源自Cancer Cell ）该研究发现前列腺癌(PCa)中突触结合细胞质RNA相互作用蛋白(SYNCRIP)的频繁丢失是一个分子驱动事件，释放APOBEC驱动的突变。在SYNCRIP缺失的肿瘤中，过度激活的APOBEC3B是PCa(包括FOXA1、EP300和AR)中频繁驱动突变的关键突变子和分子来源。研究结果确定了8个由APOBEC3B失调引起的PCa雄激素受体(AR)靶向治疗耐药的关键驱动因素。与传统认识相反，单细胞转录组学分析显示，APOBEC3B诱导的FOXA1驱动突变胜过其他驱动突变，最终主导耐药肿瘤。总的来说，这些发现揭示了控制肿瘤突变负担和异质性的细胞内在机制，并将SYNCRIP和过度激活的APOBEC3B驱动的突变与经常观察到的赋予AR靶向治疗耐药性的驱动突变在机制上联系起来。文章来源“iNature”责编|文竞择校对|文竞择End 往期精选围观历史性突破！不需卵子和精子就可以合成人类胚胎热文富豪用儿子血浆“回春”科学吗？Science：血液牛磺酸缺乏驱动衰老热文世界首例！35岁的她，通过机器人操刀移植的子宫，成功诞下宝宝热文‍为了避免心脏骤停，53岁的他成为“第一个”植入开创性除颤器的心脏病患者热文首次披露！175家生物制药公司的薪资数据：薪资中位数达20万美元点击“阅读原文”，了解更多~

基因疗法临床研究放射疗法

2023-02-26

·生物制品圈

万能蛋白被破解？加州大学最新研究揭示了肺细胞如何保护自己免受RNA病毒感染

导读：呼吸道合胞病毒（RSV）、SARS-CoV2、流感病毒、脊髓灰质炎病毒和麻疹（均为单链RNA病毒）是通过呼吸道气溶胶传播的高度传染性疾病的一些例子，这些气溶胶通常会感染肺细胞。患有慢性肺部疾病的患者，如哮喘，囊性纤维化，慢性阻塞性肺病和间质性肺疾病，更容易发生呼吸道肺部感染。这些病毒感染可以进一步促进疾病进展。近日，加州大学欧文分校领导的一项新研究揭示了一种名为APOBEC3B的蛋白质如何保护细胞免受许多不同类型的RNA病毒的侵害，如呼吸道合胞病毒（RSV）、SARS-CoV2、流感病毒、脊髓灰质炎病毒和麻疹，有助于预防疾病。研究论文“APOBEC3B drives PKR-mediated translation shutdown and protects stress granules in response to viral infection”发表在《Nature Communications》上。https://www-nature-com.libproxy1.nus.edu.sg/articles/s41467-023-36445-9APOBEC3酶 01 APOBEC3酶是先天免疫系统的重要组成部分，可抵消细胞可能遇到的各种病毒感染。APOBEC3介导的病毒基因组脱氨通过产生致命突变来阻止新病毒的产生，导致新合成的病毒蛋白功能丧失和病毒基因组降解。相比之下，由APOBEC3酶诱导的突变也可以驱动病毒进化和新的病毒变体的产生，这些变异体具有抵抗细胞防御机制的特征改变。APOBEC3所具备的脱氨活性是一把双刃剑，APOBEC3酶可能已经发展出其他机制，与诱导突变并行，以抑制病毒复制并阻止病毒进化。在这项研究中，我们发现A3B调节病毒感染不同阶段的先天免疫反应，并确定了具体的机制。首先，我们发现A3B促进PKR激活诱导的SG形成和翻译关闭，以限制病毒蛋白合成。其次，我们发现A3B保护RNA相关的SGs免受RNase L介导的RNA衰变，以促进G3BP1-RNA缩合物和SG形成。A3B驱动PKR介导的翻译停滞，保护应激颗粒免受RNase L活性的影响。A3B与PABPC1形成复合物以刺激PKR并抵消ADAR1的PKR抑制活性以响应病毒感染。此外，A3B通过与PABPC1的相互作用定位于应激颗粒，以保护与应激颗粒相关的mRNA在病毒感染期间免受RNAse L诱导的RNA切割。PKR调节 02 细胞中PKR的严格调节对于防止自身dsRNA诱导的翻译关闭至关重要，同时允许在病毒实际感染细胞时激活PKR40.在未感染的细胞中，ADAR1编辑或结合内源性自dsRNA，以阻止它们激活PKR。然而，ADAR1经常被病毒劫持以抑制PKR活化和翻译抑制，以支持病毒复制。研究中，我们确定了A3B和PABPC1之间形成的新复合物，该复合物对于在病毒感染期间诱导PKR活性至关重要。我们认为A3B和PABPC1的作用是抵消ADAR1的前病毒活性，并允许PKR激活以阻止翻译并限制病毒复制。然而，A3B和PABPC1刺激PKR的机制需要进一步研究。A3B和PABPC1 RNA的结合活性可能会阻止宿主或病毒RNA结合蛋白（RBP）包被RNA，使RNA更容易被PKR结合。典型 PKR 激活需要与至少 30 bp 长度的 dsRNA 结合。除了dsRNA的典型激活外，研究人员还提出了其他类型的RNA底物，例如具有有限二级结构和5′-三磷酸结构的单链RNA，以激活PKR。值得注意的是，许多病毒已经开发出切割或减少PABPC1以劫持宿主翻译机器的策略。因此，病毒对PABPC1的抑制对于限制病毒感染过程中的PKR活化和翻译停滞也至关重要。更重要的是，某些病毒（如登革热和寨卡病毒）促进PKR途径诱导翻译停滞，同时限制SG形成以阻断宿主mRNA翻译，并通过非规范翻译机制促进自身复制。这些观察结果表明，A3B的PKR调节不一定会导致病毒复制的减少，但也可能对病毒有益，具体取决于该病毒的类型和背景。因此，人们很容易推测A3B可以作为登革热和寨卡病毒复制的前病毒蛋白，并且在未来精确确定A3B对不同类型病毒复制的影响。研究意义 03 总而言之，该研究阐明了APOBEC3B如何在不产生病毒基因组突变和促进病毒进化的情况下促进宿主细胞的先天免疫反应。这一新发现对于开发未来的疗法以限制病毒感染和改善慢性肺病患者的健康至关重要。参考资料：https://medicalxpress.com/news/2023-02-reveals-lung-cells-rna-viral.htmlhttps://www.nature.com/articles/s41467-023-36445-9