Nature chemical biology最新文献

TOPO-seq reveals DNA topology-induced off-target activity by Cas9 and base editors TOPO-seq揭示了Cas9和碱基编辑器由DNA拓扑学诱导的脱靶活性

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-04-02 DOI: 10.1038/s41589-025-01867-7

Min Duan, Pan Gao, Yi-Zhou Zhang, Yu-Long Hu, Lei Zhou, Zhong-Chen Xu, Hou-Yuan Qiu, Xiao-Han Tong, Rui-Jin Ji, Xin-Lin Lei, Hao Yin, Cun-Lan Guo, Ying Zhang

{"title":"TOPO-seq reveals DNA topology-induced off-target activity by Cas9 and base editors","authors":"Min Duan, Pan Gao, Yi-Zhou Zhang, Yu-Long Hu, Lei Zhou, Zhong-Chen Xu, Hou-Yuan Qiu, Xiao-Han Tong, Rui-Jin Ji, Xin-Lin Lei, Hao Yin, Cun-Lan Guo, Ying Zhang","doi":"10.1038/s41589-025-01867-7","DOIUrl":"https://doi.org/10.1038/s41589-025-01867-7","url":null,"abstract":"With the increasing use of CRISPR–Cas9, detecting off-target events is essential for safety. Current methods primarily focus on guide RNA (gRNA) sequence mismatches, often overlooking the impact of DNA topology in regulating off-target activity. Here we present TOPO-seq, a high-throughput and sensitive method that identifies genome-wide off-target effects of Cas9 and base editors while accounting for DNA topology. TOPO-seq revealed that topology-induced off-target sites frequently harbor higher mismatches than the relaxed DNA sequence, with over 50% of off-target sites containing six mismatches, which are usually overlooked using previous methods. Applying TOPO-seq to three therapeutic gRNAs in hematopoietic stem cells identified 47 bona fide off-target loci, six of which are specifically induced by DNA topology. These findings highlight DNA topology as a regulator of off-target editing rates, establish TOPO-seq as a robust method for capturing DNA topology-induced off-target events and underscore its importance in off-target detection for developing safe genome-editing therapies.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"106 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Single-step discovery of high-affinity RNA ligands by UltraSelex

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-03-31 DOI: 10.1038/s41589-025-01868-6

Yaqing Zhang, Yuan Jiang, David Kuster, Qiwei Ye, Wenhao Huang, Simon Fürbacher, Jingye Zhang, Pia Doll, Wenjun Lin, Siwei Dong, Hui Wang, Zhipeng Tang, David Ibberson, Klemens Wild, Irmgard Sinning, Anthony A. Hyman, Andres Jäschke

{"title":"Single-step discovery of high-affinity RNA ligands by UltraSelex","authors":"Yaqing Zhang, Yuan Jiang, David Kuster, Qiwei Ye, Wenhao Huang, Simon Fürbacher, Jingye Zhang, Pia Doll, Wenjun Lin, Siwei Dong, Hui Wang, Zhipeng Tang, David Ibberson, Klemens Wild, Irmgard Sinning, Anthony A. Hyman, Andres Jäschke","doi":"10.1038/s41589-025-01868-6","DOIUrl":"https://doi.org/10.1038/s41589-025-01868-6","url":null,"abstract":"Aptamers, nucleic acid ligands targeting specific molecules, have emerged as drug candidates, sensors, imaging tools and nanotechnology building blocks. The predominant method for their discovery, systematic evolution of ligands by exponential enrichment, while successful, is laborious, time-consuming and often results in candidates enriched for unintended criteria. Here we present UltraSelex, a noniterative method that combines biochemical partitioning, high-throughput sequencing and computational signal-to-background rank modeling for discovering RNA aptamers in about 1 day. UltraSelex identified high-affinity RNA aptamers capable of binding a fluorogenic silicon rhodamine dye and two protein targets, the SARS-CoV-2 RNA-dependent RNA polymerase and HIV reverse transcriptase, enabling live-cell RNA imaging and efficient enzyme inhibition, respectively. From the ranked sequences, minimal aptamer motifs could be easily inferred. UltraSelex provides a rapid route to reveal new drug candidates and diagnostic tools.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"1 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Author Correction: Imaging the dynamics of messenger RNA with a bright and stable green fluorescent RNA

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-03-28 DOI: 10.1038/s41589-025-01892-6

Fangting Zuo, Li Jiang, Ni Su, Yaqiang Zhang, Bingkun Bao, Limei Wang, Yajie Shi, Huimin Yang, Xinyi Huang, Ruilong Li, Qingmei Zeng, Zhengda Chen, Qiuning Lin, Yingping Zhuang, Yuzheng Zhao, Xianjun Chen, Linyong Zhu, Yi Yang

引用次数: 0

Post-transcriptional modular synthetic receptors

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-03-28 DOI: 10.1038/s41589-025-01872-w

Xiaowei Zhang, Luis S. Mille-Fragoso, K. Eerik Kaseniit, Arden P. Lee, Meng Zhang, Connor C. Call, Yixin Hu, Yunxin Xie, Xiaojing J. Gao

引用次数: 0

Trans-splicing for gene regulation

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-03-27 DOI: 10.1038/s41589-025-01871-x

Samat Bayakhmetov, Mahan Naseri, Xiao Wang

引用次数: 0

Reversible histone deacetylase activity catalyzes lysine acylation

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-03-26 DOI: 10.1038/s41589-025-01869-5

Takeshi Tsusaka, Mohd. Altaf Najar, Benjamin Schwarz, Eric Bohrnsen, Juan A. Oses-Prieto, Helena Neudorf, Christina Lee, Jonathan P. Little, Alma L. Burlingame, Catharine M. Bosio, George M. Burslem, Emily L. Goldberg

{"title":"Reversible histone deacetylase activity catalyzes lysine acylation","authors":"Takeshi Tsusaka, Mohd. Altaf Najar, Benjamin Schwarz, Eric Bohrnsen, Juan A. Oses-Prieto, Helena Neudorf, Christina Lee, Jonathan P. Little, Alma L. Burlingame, Catharine M. Bosio, George M. Burslem, Emily L. Goldberg","doi":"10.1038/s41589-025-01869-5","DOIUrl":"https://doi.org/10.1038/s41589-025-01869-5","url":null,"abstract":"The dynamic modification of proteins by many metabolites suggests an intimate link between energy metabolism and post-translational modifications (PTMs). For instance, starvation and low-carbohydrate diets lead to the accumulation of β-hydroxybutyrate (BHB), whose blood concentrations can reach millimolar levels, concomitant with the accumulation of lysine β-hydroxybutyrylation (Kbhb) of proteins. Here we report that class I histone deacetylases (HDACs) unexpectedly catalyze the formation of Kbhb. Through mutational analysis, we show a shared reliance on key active site amino acids for classical deacetylation and noncanonical HDAC-catalyzed β-hydroxybutyrylation. On the basis of these data, we propose that HDACs catalyze a condensation reaction between the free amine group on lysine and the BHB carboxylic acid, thereby generating an amide bond. This reversible HDAC activity is not limited to BHB and extends to multiple short-chain fatty acids, representing a novel mechanism of PTM deposition relevant to metabolically sensitive proteome modifications.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"71 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143702901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pharmacological targeting of BMAL1 modulates circadian and immune pathways

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-03-25 DOI: 10.1038/s41589-025-01863-x

Hua Pu, Laura C. Bailey, Ludwig G. Bauer, Maria Voronkov, Matthew Baxter, Kilian V. M. Huber, Sepideh Khorasanizadeh, David Ray, Fraydoon Rastinejad

{"title":"Pharmacological targeting of BMAL1 modulates circadian and immune pathways","authors":"Hua Pu, Laura C. Bailey, Ludwig G. Bauer, Maria Voronkov, Matthew Baxter, Kilian V. M. Huber, Sepideh Khorasanizadeh, David Ray, Fraydoon Rastinejad","doi":"10.1038/s41589-025-01863-x","DOIUrl":"https://doi.org/10.1038/s41589-025-01863-x","url":null,"abstract":"The basic helix–loop–helix PER-ARNT-SIM (bHLH-PAS) proteins BMAL1 and CLOCK heterodimerize to form the master transcription factor governing rhythmic gene expression. Owing to connections between circadian regulation and numerous physiological pathways, targeting the BMAL1–CLOCK complex pharmacologically is an attractive entry point for intervening in circadian-related processes. In this study, we developed a small molecule, Core Circadian Modulator (CCM), that targets the cavity in the PASB domain of BMAL1, causing it to expand, leading to conformational changes in the PASB domain and altering the functions of BMAL1 as a transcription factor. Biochemical, structural and cellular investigations validate the high level of selectivity of CCM in engaging BMAL1, enabling direct access to BMAL1–CLOCK cellular activities. CCM induces dose-dependent alterations in PER2–Luc oscillations and orchestrates the downregulation of inflammatory and phagocytic pathways in macrophages. These findings collectively reveal that the BMAL1 protein architecture is inherently configured to enable the binding of chemical ligands for functional modulation.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"97 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Learning from CoQ10 history

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2025-03-24 DOI: 10.1038/s41589-025-01877-5

Francesco Zamberlan

引用次数: 0

Phage-fueled defense system

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2025-03-24 DOI: 10.1038/s41589-025-01875-7

Yiyun Song

引用次数: 0

Guiding chemoenzymatic synthesis