Cell Chemical Biology最新文献

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Bioluminescence assay of lysine deacylase sirtuin activity 赖氨酸脱乙酰酶 sirtuin 活性的生物发光测定

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology

Pub Date : 2024-11-21 DOI: 10.1016/j.chembiol.2024.10.006

Alexandria N. Van Scoyk , Orlando Antelope , Donald E. Ayer , Randall T. Peterson , Anthony D. Pomicter , Shawn C. Owen , Michael W. Deininger

Lysine acylation can direct protein function, localization, and interactions. Sirtuins deacylate lysine toward maintaining cellular homeostasis, and their aberrant expression contributes to the pathogenesis of multiple conditions, including cancer. Measuring sirtuins’ activity is essential to exploring their potential as therapeutic targets, but accurate quantification is challenging. We developed “SIRTify”, a high-sensitivity assay for measuring sirtuin activity in vitro and in vivo. SIRTify is based on a split-version of the NanoLuc luciferase consisting of a truncated, catalytically inactive N-terminal moiety (LgBiT) that complements with a high-affinity C-terminal peptide (p86) to form active luciferase. Acylation of two lysines within p86 disrupts binding to LgBiT and abates luminescence. Deacylation by sirtuins reestablishes p86 and restores binding, generating a luminescence signal proportional to sirtuin activity. Measurements accurately reflect reported sirtuin specificity for lysine-acylations and confirm the effects of sirtuin modulators. SIRTify quantifies lysine deacylation dynamics and may be adaptable to monitoring additional post-translational modifications.

赖氨酸酰化可指导蛋白质的功能、定位和相互作用。Sirtuins 对赖氨酸进行脱乙酰化，以维持细胞的平衡，而它们的异常表达则是包括癌症在内的多种疾病的发病机理之一。测量 Sirtuins 的活性对于探索其作为治疗靶点的潜力至关重要，但精确量化却很有挑战性。我们开发了 "SIRTify"，这是一种用于测量体内外 sirtuin 活性的高灵敏度检测方法。SIRTify 基于 NanoLuc 荧光素酶的分裂版本，由一个截短的、无催化活性的 N 端分子（LgBiT）与一个高亲和力的 C 端肽（p86）互补形成活性荧光素酶。p86 中两个赖氨酸的酰化会破坏与 LgBiT 的结合并减弱荧光。sirtuin 的脱酰基作用可重建 p86 并恢复结合，从而产生与 sirtuin 活性成比例的发光信号。测量结果准确反映了所报道的 sirtuin 对赖氨酸酰化的特异性，并证实了 sirtuin 调节剂的作用。SIRTify 可量化赖氨酸脱酰化动态，并可用于监测其他翻译后修饰。

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引用次数: 0

Decoding retrons: Breakthroughs in RT-DNA production and genome editing 解码 RT：RT-DNA 生产和基因组编辑方面的突破

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology

Pub Date : 2024-11-21 DOI: 10.1016/j.chembiol.2024.10.011

Wenqian Liu , Yingjia Pan , Yu Zhang , Chang Dong , Lei Huang , Jiazhang Lian

Retrons are notable for their anti-phage defense functions and genome engineering applications. However, only a few retrons have been well characterized. In the August issue of Nature Biotechnology, Khan et al.¹ present hundreds of experimentally studied retrons, which are critical for bacterial immunity research and retron-based genome engineering technologies.

视网膜因其抗噬菌体防御功能和基因组工程应用而备受关注。然而，只有少数 retrons 得到了很好的表征。在 8 月份的《自然-生物技术》（Nature Biotechnology）杂志上，Khan 等人1 介绍了数百个经过实验研究的 retrons，这对细菌免疫研究和基于 retron 的基因组工程技术至关重要。

引用次数: 0

Lipid availability influences ferroptosis sensitivity in cancer cells by regulating polyunsaturated fatty acid trafficking 脂质供应通过调节多不饱和脂肪酸的运输影响癌细胞对铁蛋白沉积的敏感性

IF 8.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology

Pub Date : 2024-10-22 DOI: 10.1016/j.chembiol.2024.09.008

Kelly H. Sokol, Cameron J. Lee, Thomas J. Rogers, Althea Waldhart, Abigail E. Ellis, Sahithi Madireddy, Samuel R. Daniels, Rachel (Rae) J. House, Xinyu Ye, Mary Olesnavich, Amy Johnson, Benjamin R. Furness, Ryan D. Sheldon, Evan C. Lien

Ferroptosis is a form of cell death caused by lipid peroxidation that is emerging as a target for cancer therapy, highlighting the need to identify factors that govern ferroptosis susceptibility. Lipid peroxidation occurs primarily on phospholipids containing polyunsaturated fatty acids (PUFAs). Here, we show that even though extracellular lipid limitation reduces cellular PUFA levels, lipid-starved cancer cells are paradoxically more sensitive to ferroptosis. Using mass spectrometry-based lipidomics with stable isotope fatty acid labeling, we show that lipid limitation induces a fatty acid trafficking pathway in which PUFAs are liberated from triglycerides to synthesize highly unsaturated PUFAs such as arachidonic and adrenic acid. These PUFAs then accumulate in phospholipids, including ether phospholipids, to promote ferroptosis sensitivity. Therefore, PUFA levels within cancer cells do not necessarily correlate with ferroptosis susceptibility. Rather, how cancer cells respond to extracellular lipid levels by trafficking PUFAs into proper phospholipid pools contributes to their sensitivity to ferroptosis.

铁中毒是由脂质过氧化引起的一种细胞死亡形式，正逐渐成为癌症治疗的靶点，这突出表明有必要确定影响铁中毒易感性的因素。脂质过氧化主要发生在含有多不饱和脂肪酸（PUFA）的磷脂上。在这里，我们发现即使细胞外脂质限制降低了细胞中的多不饱和脂肪酸水平，但缺脂的癌细胞却对铁中毒更为敏感。利用基于质谱的脂质组学和稳定同位素脂肪酸标记，我们发现脂质限制诱导脂肪酸贩运途径，其中 PUFA 从甘油三酯中释放出来，合成高度不饱和的 PUFA，如花生四烯酸和肾上腺酸。然后，这些 PUFAs 会在磷脂（包括醚磷脂）中积聚，从而促进铁变态反应的敏感性。因此，癌细胞内的 PUFA 含量并不一定与铁中毒敏感性相关。相反，癌细胞如何通过将 PUFA 转化为适当的磷脂池来对细胞外脂质水平做出反应，才会导致其对铁中毒的敏感性。

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引用次数: 0

A tau dephosphorylation-targeting chimeraselectively recruits protein phosphatase-1 to ameliorate Alzheimer’s disease and tauopathies 牛头去磷酸化靶向嵌合酶选择性招募蛋白磷酸酶-1，改善阿尔茨海默病和牛头病的病情

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology

Pub Date : 2024-10-17 DOI: 10.1016/j.chembiol.2024.09.003

Yue Xiao , Linyu Wei , Jingfen Su , Huiyang Lei , Fei Sun , Mengzhu Li , Shihong Li , Xiaochuan Wang , Jie Zheng , Jian-Zhi Wang

Abnormal accumulation of hyperphosphorylated tau (pTau) is a major cause of neurodegeneration in Alzheimer’s disease (AD) and related tauopathies. Therefore, reducing pTau holds therapeutic promise for these diseases. Here, we developed a chimeric peptide, named D20, for selective facilitation of tau dephosphorylation by recruiting protein phosphatase 1 (PP1) to tau. PP1 is one of the active phosphatases that dephosphorylates tau. In both cultured primary hippocampal neurons and mouse models for AD or related tauopathies, we demonstrated that single-dose D20 treatment significantly reduced pTau by dephosphorylation at multiple AD-related sites and total tau (tTau) levels were also decreased. Multiple-dose administration of D20 through tail vein injection in 3xTg AD mice effectively ameliorated tau-associated pathologies with improved cognitive functions. Importantly, at therapeutic doses, D20 did not cause detectable toxicity in cultured neurons, neural cells, or peripheral organs in mice. These results suggest that D20 is a promising drug candidate for AD and related tauopathies.

高磷酸化 tau（pTau）的异常积累是阿尔茨海默病（AD）和相关 tau 病神经变性的主要原因。因此，降低 pTau 有望治疗这些疾病。在这里，我们开发了一种名为D20的嵌合肽，通过将蛋白磷酸酶1（PP1）招募到tau上，选择性地促进tau去磷酸化。PP1是使tau去磷酸化的活性磷酸酶之一。我们在培养的原代海马神经元和AD或相关tau病小鼠模型中证实，单剂量D20治疗可通过在多个AD相关位点去磷酸化而显著降低pTau，总tau（tTau）水平也会降低。在 3xTg AD 小鼠中通过尾静脉注射多剂量 D20 能有效改善与 tau 相关的病理现象，并改善认知功能。重要的是，在治疗剂量下，D20 不会对小鼠的培养神经元、神经细胞或外周器官产生可检测到的毒性。这些结果表明，D20是一种很有前景的候选药物，可用于治疗AD和相关的tau病症。

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引用次数: 0

Engineering acyclovir-induced RNA nanodevices for reversible and tunable control of aptamer function 设计阿昔洛韦诱导的 RNA 纳米器件，实现对适配体功能的可逆和可调控制。

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology

Pub Date : 2024-10-17 DOI: 10.1016/j.chembiol.2024.07.017

Timo Hagen , Jacob L. Litke , Nahian Nasir , Qian Hou , Samie R. Jaffrey

Small molecule-regulated RNA devices have the potential to modulate diverse aspects of cellular function, but the small molecules used to date have potential toxicities limiting their use in cells. Here we describe a method for creating drug-regulated RNA nanodevices (RNs) using acyclovir, a biologically compatible small molecule with minimal toxicity. Our modular approach involves a scaffold comprising a central F30 three-way junction, an integrated acyclovir aptamer on the input arm, and a variable effector-binding aptamer on the output arm. This design allows for the rapid engineering of acyclovir-regulated RNs, facilitating temporal, tunable, and reversible control of intracellular aptamers. We demonstrate the control of the Broccoli aptamer and the iron-responsive element (IRE) by acyclovir. Regulating the IRE with acyclovir enables precise control over iron-regulatory protein (IRP) sequestration, consequently promoting the inhibition of ferroptosis. Overall, the method described here provides a platform for transforming aptamers into acyclovir-controllable antagonists against physiologic target proteins.

小分子调控的 RNA 装置有可能调节细胞功能的各个方面，但迄今为止使用的小分子具有潜在毒性，限制了它们在细胞中的使用。在这里，我们介绍了一种利用阿昔洛韦（一种生物相容性极好、毒性极低的小分子）制造药物调控 RNA 纳米器件（RN）的方法。我们的模块化方法包括一个由中央 F30 三向接头、输入臂上的集成阿昔洛韦适配体和输出臂上的可变效应物结合适配体组成的支架。这种设计可以快速设计阿昔洛韦调控的 RN，促进对细胞内适配体的时间性、可调性和可逆性控制。我们展示了阿昔洛韦对 Broccoli aptamer 和铁反应元件 (IRE) 的控制。用阿昔洛韦调控 IRE 可以精确控制铁调节蛋白（IRP）的螯合，从而促进对铁突变的抑制。总之，本文介绍的方法为将适配体转化为阿昔洛韦可控的生理靶蛋白拮抗剂提供了一个平台。

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引用次数: 0

Small molecules targeting selective PCK1 and PGC-1α lysine acetylation cause anti-diabetic action through increased lactate oxidation 以选择性 PCK1 和 PGC-1α 赖氨酸乙酰化为靶点的小分子通过增加乳酸氧化作用发挥抗糖尿病作用

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology

Pub Date : 2024-10-17 DOI: 10.1016/j.chembiol.2024.09.001

Beste Mutlu , Kfir Sharabi , Jee Hyung Sohn , Bo Yuan , Pedro Latorre-Muro , Xin Qin , Jin-Seon Yook , Hua Lin , Deyang Yu , João Paulo G. Camporez , Shingo Kajimura , Gerald I. Shulman , Sheng Hui , Theodore M. Kamenecka , Patrick R. Griffin , Pere Puigserver

Small molecules selectively inducing peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α acetylation and inhibiting glucagon-dependent gluconeogenesis causing anti-diabetic effects have been identified. However, how these small molecules selectively suppress the conversion of gluconeogenic metabolites into glucose without interfering with lipogenesis is unknown. Here, we show that a small molecule SR18292 inhibits hepatic glucose production by increasing lactate and glucose oxidation. SR18292 increases phosphoenolpyruvate carboxykinase 1 (PCK1) acetylation, which reverses its gluconeogenic reaction and favors oxaloacetate (OAA) synthesis from phosphoenolpyruvate. PCK1 reverse catalytic reaction induced by SR18292 supplies OAA to tricarboxylic acid (TCA) cycle and is required for increasing glucose and lactate oxidation and suppressing gluconeogenesis. Acetylation mimetic mutant PCK1 K91Q favors anaplerotic reaction and mimics the metabolic effects of SR18292 in hepatocytes. Liver-specific expression of PCK1 K91Q mutant ameliorates hyperglycemia in obese mice. Thus, SR18292 blocks gluconeogenesis by enhancing gluconeogenic substrate oxidation through PCK1 lysine acetylation, supporting the anti-diabetic effects of these small molecules.

目前已经发现了一些小分子，它们能选择性地诱导过氧化物酶体增殖体激活受体-γ 辅激活剂（PGC）-1α 乙酰化，抑制胰高血糖素依赖性葡萄糖生成，从而产生抗糖尿病作用。然而，这些小分子如何选择性地抑制糖元代谢产物转化为葡萄糖而不干扰脂肪生成尚不清楚。在这里，我们发现小分子 SR18292 可通过增加乳酸和葡萄糖氧化来抑制肝糖生成。SR18292 可增加磷酸烯醇丙酮酸羧激酶 1（PCK1）的乙酰化，从而逆转其葡萄糖生成反应，有利于从磷酸烯醇丙酮酸合成草酰乙酸（OAA）。SR18292 诱导的 PCK1 反向催化反应为三羧酸（TCA）循环提供 OAA，是增加葡萄糖和乳酸氧化以及抑制葡萄糖生成所必需的。乙酰化模拟突变体 PCK1 K91Q 有利于无乙酰化反应，并能模拟 SR18292 在肝细胞中的代谢作用。肝脏特异性表达 PCK1 K91Q 突变体可改善肥胖小鼠的高血糖症状。因此，SR18292 通过 PCK1 赖氨酸乙酰化增强糖原底物氧化，从而阻断糖原生成，支持这些小分子药物的抗糖尿病作用。

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引用次数: 0

The anti-tubercular callyaerins target the Mycobacterium tuberculosis-specific non-essential membrane protein Rv2113 以结核分枝杆菌特异性非必需膜蛋白 Rv2113 为靶标的抗结核药草素

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology

Pub Date : 2024-10-17 DOI: 10.1016/j.chembiol.2024.06.002

Spread of antimicrobial resistances urges a need for new drugs against Mycobacterium tuberculosis (Mtb) with mechanisms differing from current antibiotics. Previously, callyaerins were identified as promising anti-tubercular agents, representing a class of hydrophobic cyclopeptides with an unusual (Z)-2,3-di-aminoacrylamide unit. Here, we investigated the molecular mechanisms underlying their antimycobacterial properties. Structure-activity relationship studies enabled the identification of structural determinants relevant for antibacterial activity. Callyaerins are bacteriostatics selectively active against Mtb, including extensively drug-resistant strains, with minimal cytotoxicity against human cells and promising intracellular activity. By combining mutant screens and various chemical proteomics approaches, we showed that callyaerins target the non-essential, Mtb-specific membrane protein Rv2113, triggering a complex dysregulation of the proteome, characterized by global downregulation of lipid biosynthesis, cell division, DNA repair, and replication. Our study thus identifies Rv2113 as a previously undescribed Mtb-specific drug target and demonstrates that also non-essential proteins may represent efficacious targets for antimycobacterial drugs.

抗菌素耐药性的蔓延促使人们需要机制不同于现有抗生素的抗结核杆菌（Mtb）新药。此前，茜草素被认为是一种很有前景的抗结核药物，它代表了一类具有不寻常 (Z)-2,3 二氨基丙烯酰胺单元的疏水性环肽。在这里，我们研究了其抗结核特性的分子机制。通过结构-活性关系研究，我们确定了与抗菌活性相关的结构决定因素。Callyaerins是一种抑菌剂，对Mtb（包括广泛耐药菌株）具有选择性活性，对人体细胞的细胞毒性极小，而且具有良好的细胞内活性。通过结合突变体筛选和各种化学蛋白质组学方法，我们发现卡来霉素以非必需的、Mtb 特异性膜蛋白 Rv2113 为靶标，引发了复杂的蛋白质组失调，其特征是脂质生物合成、细胞分裂、DNA 修复和复制的全面下调。因此，我们的研究将 Rv2113 确定为以前未曾描述过的 Mtb 特异性药物靶点，并证明非必要蛋白也可能是抗霉菌药物的有效靶点。

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引用次数: 0

Dissecting the neuroprotective interaction between the BH4 domain of BCL-w and the IP3 receptor 剖析 BCL-w 的 BH4 结构域与 IP3 受体之间的神经保护相互作用

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology

Pub Date : 2024-10-17 DOI: 10.1016/j.chembiol.2024.06.016

Sophia X. Tang , Christina M. Camara , Joy A. Franco , Maria F. Pazyra-Murphy , Yihang Li , Marina Godes , Benjamin M. Moyer , Gregory H. Bird , Rosalind A. Segal , Loren D. Walensky

BCL-w is a BCL-2 family protein that promotes cell survival in tissue- and disease-specific contexts. The canonical anti-apoptotic functionality of BCL-w is mediated by a surface groove that traps the BCL-2 homology 3 (BH3) α-helices of pro-apoptotic members, blocking cell death. A distinct N-terminal portion of BCL-w, termed the BCL-2 homology 4 (BH4) domain, selectively protects axons from paclitaxel-induced degeneration by modulating IP3 receptors, a noncanonical BCL-2 family target. Given the potential of BCL-w BH4 mimetics to prevent or mitigate chemotherapy-induced peripheral neuropathy, we sought to characterize the interaction between BCL-w BH4 and the IP3 receptor, combining “staple” and alanine scanning approaches with molecular dynamics simulations. We generated and identified stapled BCL-w BH4 peptides with optimized IP3 receptor binding and neuroprotective activities. Point mutagenesis further revealed the sequence determinants for BCL-w BH4 specificity, providing a blueprint for therapeutic targeting of IP3 receptors to achieve neuroprotection.

BCL-w是一种BCL-2家族蛋白，可在组织和疾病特异性环境中促进细胞存活。BCL-w 的典型抗凋亡功能由一个表面沟槽介导，该沟槽能捕获促凋亡成员的 BCL-2 同源 3 (BH3) α-螺旋，从而阻止细胞死亡。BCL-w的一个独特的N端部分被称为BCL-2同源4（BH4）结构域，它通过调节IP3受体（BCL-2家族的一个非经典靶点），选择性地保护轴突免受紫杉醇诱导的变性。鉴于 BCL-w BH4 拟定物有可能预防或减轻化疗诱导的周围神经病变，我们将 "钉书针 "和丙氨酸扫描方法与分子动力学模拟相结合，试图描述 BCL-w BH4 与 IP3 受体之间的相互作用。我们生成并鉴定了具有优化的 IP3 受体结合和神经保护活性的订书钉 BCL-w BH4 肽。点突变进一步揭示了 BCL-w BH4 特异性的序列决定因素，为靶向 IP3 受体实现神经保护提供了治疗蓝图。

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引用次数: 0

Plant synthetic genomics: Big lessons from the little yeast 植物合成基因组学：从小酵母中汲取大教训

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology

Pub Date : 2024-10-17 DOI: 10.1016/j.chembiol.2024.08.001

Hao Ye , Guangyu Luo , Zhenwu Zheng , Xiaofang Li , Jie Cao , Jia Liu , Junbiao Dai

Yeast has been extensively studied and engineered due to its genetic amenability. Projects like Sc2.0 and Sc3.0 have demonstrated the feasibility of constructing synthetic yeast genomes, yielding promising results in both research and industrial applications. In contrast, plant synthetic genomics has faced challenges due to the complexity of plant genomes. However, recent advancements of the project SynMoss, utilizing the model moss plant Physcomitrium patens, offer opportunities for plant synthetic genomics. The shared characteristics between P. patens and yeast, such as high homologous recombination rates and dominant haploid life cycle, enable researchers to manipulate P. patens genomes similarly, opening promising avenues for research and application in plant synthetic biology. In conclusion, harnessing insights from yeast synthetic genomics and applying them to plants, with P. patens as a breakthrough, shows great potential for revolutionizing plant synthetic genomics.

酵母因其遗传适应性而被广泛研究和改造。Sc2.0和Sc3.0等项目证明了构建合成酵母基因组的可行性，在研究和工业应用方面都取得了可喜的成果。相比之下，由于植物基因组的复杂性，植物合成基因组学一直面临挑战。不过，最近利用模式苔藓植物斑叶蕨藻（Physcomitrium patens）开展的 "SynMoss "项目取得的进展为植物合成基因组学提供了机遇。青苔和酵母的共同特点，如高同源重组率和显性单倍体生命周期，使研究人员能够对青苔基因组进行类似的操作，为植物合成生物学的研究和应用开辟了广阔的前景。总之，利用酵母合成基因组学的洞察力并将其应用于植物，以冬青树为突破口，显示出植物合成基因组学革命的巨大潜力。

引用次数: 0

Reducing CRISPR-Cas9 off-target effects by optically controlled chemical modifications of guide RNA 通过光控化学修饰引导 RNA 减少 CRISPR-Cas9 的脱靶效应

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology

Pub Date : 2024-10-17 DOI: 10.1016/j.chembiol.2024.09.006

Qianqian Qi , Xingyu Liu , Wei Xiong , Kaisong Zhang , Wei Shen , Yuanyuan Zhang , Xinyan Xu , Cheng Zhong , Yan Zhang , Tian Tian , Xiang Zhou

A photocatalytic click chemistry approach, offering a significant advancement over conventional methods in RNA function modulation is described. This innovative method, utilizing light-activated small molecules, provides a high level of precision and control in RNA regulation, particularly effective in intricate cellular processes. By applying this strategy to CRISPR-Cas9 gene editing, we demonstrate its effectiveness in enhancing gene editing specificity and markedly reducing off-target effects. Our approach employs a vinyl ether modification in RNA, which activated under visible light with a phenanthrenequinone derivative, creating a CRISPR-OFF switch that precisely regulates CRISPR system activity. This method not only represents an advancement in genomic interventions but also offers broad applications in gene regulation, paving the way for safer and more reliable gene editing in therapeutic genomics.

本文介绍了一种光催化点击化学方法，与传统的 RNA 功能调节方法相比，这种方法具有重大进步。这种创新方法利用光激活的小分子，提供了高水平的 RNA 调节精度和控制能力，在复杂的细胞过程中尤其有效。通过将这种策略应用于 CRISPR-Cas9 基因编辑，我们证明了它在增强基因编辑特异性和显著减少脱靶效应方面的有效性。我们的方法在 RNA 中采用乙烯基醚修饰，在可见光下用菲醌衍生物激活，形成一个 CRISPR-OFF 开关，精确调节 CRISPR 系统的活性。这种方法不仅代表了基因组干预技术的进步，而且在基因调控方面具有广泛的应用前景，为在治疗基因组学中进行更安全、更可靠的基因编辑铺平了道路。

引用次数: 0

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