更新于：2024-05-01

RAD18

RAD18 E3 ubiquitin protein ligase

更新于：2024-05-01

基本信息

别名

E3 ubiquitin-protein ligase RAD18、hHR18、hRAD18

+ [6]

简介

E3 ubiquitin-protein ligase involved in postreplication repair of UV-damaged DNA. Postreplication repair functions in gap-filling of a daughter strand on replication of damaged DNA. Associates to the E2 ubiquitin conjugating enzyme UBE2B to form the UBE2B-RAD18 ubiquitin ligase complex involved in mono-ubiquitination of DNA-associated PCNA on 'Lys-164'. Has ssDNA binding activity.

关联

100 项与 RAD18 相关的临床结果

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100 项与 RAD18 相关的转化医学

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0 项与 RAD18 相关的专利（医药）

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512

项与 RAD18 相关的文献（医药）

2024-01-18·Microbiological research

Rad6, a ubiquitin conjugator required for insect-pathogenic lifestyle, UV damage repair, and genomic expression of Beauveria bassiana.

Article

作者: Xin-Cheng Luo ; Lei Yu ; Si-Yuan Xu ; Sheng-Hua Ying ; Ming-Guang Feng

The E2 ubiquitin conjugator Rad6 is required for DNA damage bypass in budding yeast but remain functionally unknown in filamentous fungi. Here, we report pleiotropic effect of Rad6 ortholog in Beauveria bassiana, a wide-spectrum fungal insecticide. Global ubiquitination signal was greatly attenuated in the absence of rad6. The blocked ubiquitination led to severe growth defect, blocked asexual development, and abolished infectivity/insect pathogenicity, which correlated with compromised conidial quality (including viability, hydrophobicity, adherence to insect cuticle, and thermotolerance) and blocked secretion of cuticle-degrading enzymes including Pr1 family proteases. Importantly, Rad6 played much greater role in photoreactivation of UVB-impaired conidia by a 3- or 5-h light plus 9- or 7-h dark incubation than in dark reactivation of those impaired conidia by a 12-h dark incubation. The high activity of Rad6 in photoreactivation in vivo was derived from its link to a protein complex cored by the photolyase regulators WC1 and WC2 via the strong interactions of Rad6 with the E3 partner Rad18 and Rad18 with WC2 revealed in yeast two-hybrid assays. Transcriptomic analysis resulted in identification of 2700 differentially regulated genes involved in various function categories and metabolism pathways, indicating a regulatory role of Rad6-mediated ubiquitination in gene expression networks and genomic stability. Conclusively, Rad6 is required for asexual and insect-pathogenic lifecycles, solar UV damage repair, and genomic expression of B. bassiana. The primary dependence of its strong anti-UV role on photoreactivation in vivo unveils a scenario distinct from the core role of its yeast ortholog in DNA damage bypass.

2024-01-03·Cell reports

TREX2 deficiency suppresses spontaneous and genotoxin-associated mutagenesis.

Article

作者: Teresa Marple ; Mi Young Son ; Xiaodong Cheng ; Jun Ho Ko ; Patrick Sung ; Paul Hasty

TREX2, a 3'-5' exonuclease, is a part of the DNA damage tolerance (DDT) pathway that stabilizes replication forks (RFs) by ubiquitinating PCNA along with the ubiquitin E3 ligase RAD18 and other DDT factors. Mismatch repair (MMR) corrects DNA polymerase errors, including base mismatches and slippage. Here we demonstrate that TREX2 deletion reduces mutations in cells upon exposure to genotoxins, including those that cause base lesions and DNA polymerase slippage. Importantly, we show that TREX2 generates most of the spontaneous mutations in MMR-mutant cells derived from mice and people. TREX2-induced mutagenesis is dependent on the nuclease and DNA-binding attributes of TREX2. RAD18 deletion also reduces spontaneous mutations in MMR-mutant cells, albeit to a lesser degree. Inactivation of both MMR and TREX2 additively increases RF stalls, while it decreases DNA breaks, consistent with a synthetic phenotype.

2023-12-01·Cancer innovation

Current insights into the oncogenic roles of lncRNA LINC00355

Review

作者: Shen, Jinze ; Su, Xinming ; Pan, Ming ; Wang, Zehua ; Ke, Yufei ; Wang, Qurui ; Dong, Jingyin ; Duan, Shiwei

Long noncoding RNAs (lncRNAs) are a class of nonprotein-coding transcripts that are longer than 200 nucleotides. LINC00355 is a lncRNA located on chromosome 13q21.31 and is consistently upregulated in various cancers. It regulates the expression of downstream genes at both transcriptional and posttranscriptional levels, including eight microRNAs (miR-15a-5p, miR-34b-5p, miR-424-5p, miR-1225, miR-217-5p, miR-6777-3p, miR-195, and miR-466) and three protein-coding genes (ITGA2, RAD18, and UBE3C). LINC00355 plays a role in regulating various biological processes such as cell cycle progression, proliferation, apoptosis, epithelial-mesenchymal transition, invasion, and metastasis of cancer cells. It is involved in the regulation of the Wnt/β-catenin signaling pathway and p53 signaling pathway. Upregulation of LINC00355 has been identified as a high-risk factor in cancer patients and its increased expression is associated with poorer overall survival, recurrence-free survival, and disease-free survival. LINC00355 upregulation has been linked to several unfavorable clinical characteristics, including advanced tumor node metastasis and World Health Organization stages, reduced Karnofsky Performance Scale scores, increased tumor size, greater depth of invasion, and more extensive lymph node metastasis. LINC00355 induces chemotherapy resistance in cancer cells by regulating five downstream genes, namely HMGA2, ABCB1, ITGA2, WNT10B, and CCNE1 genes. In summary, LINC00355 is a potential oncogene with great potential as a diagnostic marker and therapeutic target for cancer.

项与 RAD18 相关的新闻（医药）

2024-03-18

·今日头条

本文为转化医学网原创，转载请注明出处作者：Yang Yang 导读： GBM因其极高的侵袭性和复杂的治疗耐药机制，成为神经肿瘤研究中的一大挑战。 3月4日，北卡罗来纳大学（University of North Carolina at Chapel Hill, UNC）杨阳、Cyrus Vaziri课题组（共同通讯作者），重庆大学附属肿瘤医院程兴博士和哈尔滨医科大学安静博士（并列第一作者），以及博士研究生楼继通 (UNC)、顾琦盛（中科院上海免疫与感染研究所）等在期刊《Nature Communications》上联合发表了题为“Trans-lesion synthesis and mismatch repair pathway crosstalk defines chemoresistance and hypermutation mechanisms in glioblastoma”的研究论文。研究人员揭示了跨损伤合成（Trans-lesion synthesis, TLS）和错配修复（Mismatch repair, MMR）通路间的相互作用，这一发现为理解胶质母细胞瘤（Glioblastoma，GBM）中的化疗耐药和高变异机制提供了新的视角。 https://www-nature-com.libproxy1.nus.edu.sg/articles/s41467-024-45979-5 研究背景 01 GBM是一种高度恶性的脑肿瘤，治疗难度大，预后不佳。传统治疗方法包括手术、放疗及化疗，其中替莫唑胺（Temozolomide, TMZ）是目前唯一的一线化疗药物。TMZ能引起DNA损伤，特别是O6-甲基鸟嘌呤（O6-Methylguanine, O6mG）的形成，进而阻断DNA复制和细胞周期，导致细胞死亡。然而，大多数GBM病例对TMZ存在原发抗性，或在治疗过程中快速发展出耐药性，导致疾病复发。尽管TMZ诱导的DNA损伤响应和修复机制已被部分阐明，但具体如何影响GBM细胞的化疗耐药和超突变性仍不完全清楚。研究进展 02 E3泛素连接酶RAD18（介导TLS）和MMR通路的相互作用对于理解GBM的TMZ耐药性至关重要。本研究表明，RAD18在TMZ处理的GBM细胞中被激活，并通过MMR依赖方式促进了TMZ诱发的DNA单链断裂缺口填充和细胞存活。敲除RAD18后能够显著增加GBM细胞对TMZ的敏感性。进一步，通过CRISPR筛选揭示了RAD18与多个DNA损伤应答（DDR）通路的交互作用，帮助GBM细胞耐受TMZ的毒性。对TMZ处理后GBM细胞的突变特征分析，揭示了RAD18介导无错损伤旁路（error-free lesion bypass）修复DNA单链缺口，终止由于O6mG:T错配引发且具有高度细胞毒性的MMR无效循环(Mismatch repair futile cycling)，促使细胞耐受TMZ并且降低TMZ诱发的C>T的突变（见图）。同时，RAD18还介导易错损伤旁路（error-prone lesion bypass）修复其他TMZ诱导的DNA损伤，与碱基切除修复通路（Base excision repair , BER）有联合致死作用。此外，研究还发现使用TMZ治疗的GBM患者中，低RAD18表达与复发时的超突变相关，这进一步证实了RAD18在GBM化疗耐药和超突变中的关键作用。 RAD18介导TMZ诱导的DNA损伤修复示意图研究结论 03 本研究揭示了RAD18与MMR通路的交互在TMZ抗性和GBM基因组超突变中的核心作用。RAD18的激活是GBM细胞对抗TMZ诱导DNA损伤的关键机制。本研究扩展了对TMZ耐药分子机制的认识，也为针对RAD18途径的新疗法开发提供了可能性。参考资料： https://www-nature-com.libproxy1.nus.edu.sg/articles/s41467-024-45979-5 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 上海｜06月14日-16日 ▶ 第六届上海国际癌症大会将于6月14-16日在上海举办，学科交叉，共同推进肿瘤研究与诊治多模态！ 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！点击对应文字查看详情

基因疗法临床研究

2022-11-01

·生物谷

CD：肺癌为何会对一代又一代的EGFR-TKI耐药？这个研究破案了！

全球每年约有220万人罹患肺癌，180万人死于肺癌[1]，肺癌严重威胁人类生命健康。EGFR突变是最常见的肺癌突变类型，尤其在包括中国在内的亚洲地区。全球每年约有220万人罹患肺癌，180万人死于肺癌[1]，肺癌严重威胁人类生命健康。EGFR突变是最常见的肺癌突变类型，尤其在包括中国在内的亚洲地区。自2002年问世以来，针对EGFR突变的酪氨酸激酶抑制剂（EGFR-TKI），大大延长了肺癌患者的生存时间，已成为EGFR突变肺癌一线治疗的最佳选择。可是，道高一尺，魔高一丈。EGFR-TKI应用一段时间后，患者不可避免地出现耐药，成为制约肺癌靶向治疗的一个难点[2]。为克服耐药，EGFR-TKI不断更新换代，“打补丁”式地进行完善，从以吉非替尼为代表的一代，到以奥希替尼为代表的三代，再到临床试验中的四代，一代更比一代强，然而，耐药依旧层出不穷。治疗过程中产生新突变，是肺癌获得性耐药的一个重要原因[3]。如对一代和二代TKI耐药的T790M突变，对三代TKI耐药的C797S突变。但是，其详细机制尚有待阐明。近日，由以色列魏茨曼科学研究所Yosef Yarden领衔的研究团队，揭示了肺癌经EGFR-TKI治疗产生耐药突变的机制，相关论文发表于肿瘤学顶级期刊Cancer Discovery上[4]。他们发现，肺癌细胞经EGFR-TKI刺激后，AXL被激活。AXL一方面激活RAD18，启动DNA易错旁路修复机制，加速耐药突变的出现；另一方面激活MYC，调控嘌呤合成，使核苷酸库失衡，增强诱变。如果在EGFR-TKI的治疗中联用抗AXL抗体，能抑制耐药性的产生，防止肺癌复发。官网论文首页截图研究伊始，研究人员使用EGFR-TKI处理肺癌细胞，获得不同程度的耐药亚克隆细胞，对这些细胞进行转录组测序，发现GAS6是持久耐药细胞中最明显的高表达基因。与此同时，来自临床的样本也发现，EGFR-TKI治疗失败的肺癌患者也高表达GAS6。既往研究发现，GAS6及其受体AXL在癌症中参与了肿瘤细胞的增殖和转移[5]。研究人员对AXL在肺癌中的表达进行检测，发现TKI治疗后复发的肺癌小鼠AXL表达升高，AXL磷酸化水平也上调。这提示GAS6-AXL轴可能还参与肺癌的TKI耐药。为了检验假说，研究人员分别过表达和敲除肺癌细胞的AXL，然后把细胞暴露于EGFR-TKI。相比于野生型的肺癌细胞，AXL过表达细胞存活率增加，而AXL敲除细胞存活率降低。接着，研究人员又在体内对AXL的促耐药作用进行了验证，把AXL过表达肺癌细胞和AXL敲除细胞分别接种于裸鼠，然后用TKI治疗荷瘤小鼠。AXL过表达的肺癌小鼠更早地出现耐药，AXL敲除的肺癌小鼠则完全没有复发现象。这些结果表明，GAS6-AXL轴被TKI治疗激活后，促进了肺癌细胞耐药。 AXL过表达的肺癌小鼠生长加快，AXL敲除的肺癌小鼠肿瘤生长减慢我们都知道，DNA损伤是对细胞的致命打击，为应对DNA损伤，细胞会启动DNA修复机制。TLS聚合酶参与DNA损伤修复，直接在损伤的DNA上掺入核苷酸，延续DNA复制。而TKI的作用机制之一即是破坏细胞对DNA损伤的修复能力[6]。于是，研究人员检测了TKI治疗后肺癌细胞的DNA损伤和修复情况。经TKI处理后，肺癌细胞DNA双链断裂，产生ROS，凋亡增加，存活下降，RAD18和TLS聚合酶等DNA修复相关酶表达上调。而在AXL过表达后，肺癌细胞能抵抗TKI的打击，DNA断裂减少，ROS水平降低，凋亡被抑制，存活率升高，RAD18和TLS聚合酶的表达上调至更高水平。 RAD18是一种E3泛素连接酶，通过诱导PCNA单泛素化和招募TLS聚合酶来激活DNA的易错旁路修复[7]。易错旁路途径虽然能提高细胞对DNA损伤的耐受性，但却牺牲了复制的保真度，它在损伤的DNA模板对侧掺入错误的核苷酸，引发基因组突变。研究人员对AXL和RAD18的关系进行了探究，发现AXL能与RAD18结合，增强RAD18的类泛素化，减少RAD18的泛素化，因而增强RAD18对PCNA的单泛素化修饰，进而启动易错旁路途径。接着，研究人员检测了TKI治疗后肺癌的基因组变化情况，发现TKI诱导了DNA的碱基改变，耐药突变T790M开始出现。AXL的表达水平和肺癌的突变负担呈正相关，过表达AXL能增加T790M突变频率，使用抗AXL抗体处理肺癌细胞，可显著降低T790M突变的丰度。这些结果表明，AXL促进了TKI对肺癌诱导的RAD18和TLS聚合酶表达上调，激活了易错旁路途径，加速了耐药突变的产生。 AXL能提高T790M耐药突变频率，抗AXL抗体可显著降低T790M突变对AXL调控的通路进行分析，研究人员发现AXL能影响肺癌细胞的核苷酸代谢，主要是嘌呤、组氨酸和谷氨酰胺途径。由于DNA的复制取决于脱氧核苷酸池[8]，研究人员推测，AXL可能还通过核苷酸代谢，进一步增强诱变作用。研究人员分别过表达和敲除AXL，发现肺癌细胞嘌呤代谢相关基因的表达，以及嘌呤合成途径中的代谢物也相应地发生变化。同位素标记实验显示，AXL加速了嘌呤的合成。 MYC是AXL的转录靶点，在肺癌中，MYC的表达和AXL呈正相关，而MYC能调控嘌呤合成酶。因此，研究人员得出结论，AXL通过激活MYC促进嘌呤合成，进而增强肺癌的获得性突变。最后，研究人员开发出了一种抗AXL抗体，分别在体内外检测抑制AXL对TKI疗效的增强作用。在EGFR-TKI的治疗中联用抗AXL抗体，肺癌细胞的AXL、RAD18和TLS聚合酶表达下调，凋亡增加，耐药细胞减少。动物实验表明，相比于单药治疗后出现复发，肺癌小鼠在联合用药后完全无复发。抗AXL抗体能抑制肺癌的TKI耐药，消除复发。 EGFR-TKI治疗联用抗AXL抗体能抑制肺癌生长，防止复发总的来说，研究人员发现暴露于EGFR-TKI后，肺癌细胞激活了GAS6-AXL途径，AXL同时通过非转录和转录这两种方式促进耐药突变的产生。非转录方式通过增强类泛素化和减少泛素化激活RAD18，RAD18招募TLS聚合酶启动易错旁路途径。转录方式通过激活MYC促进嘌呤合成，进而使肺癌细胞的核苷酸库失衡。这项研究不仅揭示了肺癌在EGFR-TKI治疗后出现耐药的机制，也用实验证明靶向AXL是消除EGFR突变型肺癌耐药的一个潜在策略。参考文献 [1] Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-249. [2] Nagano T, Tachihara M, Nishimura Y. Mechanism of Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors and a Potential Treatment Strategy. Cells. 2018;7(11):212. Published 2018 Nov 15. doi:10.3390/cells7110212 [3] Garraway LA, Jänne PA. Circumventing cancer drug resistance in the era of personalized medicine. Cancer Discov. 2012;2(3):214-226. doi:10.1158/2159-8290.CD-12-0012 [4] Noronha A, Belugali Nataraj N, Sang Lee J, et al. AXL and error-prone DNA replication confer drug resistance and offer strategies to treat EGFR-mutant lung cancer [published online ahead of print, 2022 Jul 27]. Cancer Discov. 2022;CD-22-0111. doi:10.1158/2159-8290.CD-22-0111 [5] Wu G, Ma Z, Hu W, et al. Molecular insights of Gas6/TAM in cancer development and therapy. Cell Death Dis. 2017;8(3):e2700. Published 2017 Mar 23. doi:10.1038/cddis.2017.113 [6] Liang XM, Qin Q, Liu BN, et al. Targeting DNA-PK overcomes acquired resistance to third-generation EGFR-TKI osimertinib in non-small-cell lung cancer. Acta Pharmacol Sin. 2021;42(4):648-654. doi:10.1038/s41401-020-00577-1 [7] Stelter P, Ulrich HD. Control of spontaneous and damage-induced mutagenesis by SUMO and ubiquitin conjugation. Nature. 2003;425(6954):188-191. doi:10.1038/nature01965 [8] Schmidt TT, Reyes G, Gries K, et al. Alterations in cellular metabolism triggered by URA7 or GLN3 inactivation cause imbalanced dNTP pools and increased mutagenesis. Proc Natl Acad Sci U S A. 2017;114(22):E4442-E4451. doi:10.1073/pnas.1618714114