Nucleic Acids Research最新文献

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Ultra-fast variant effect prediction using biophysical transcription factor binding models 利用生物物理转录因子结合模型的超快速变异效应预测
IF 14.9 2区 生物学
Nucleic Acids Research Pub Date : 2025-10-04 DOI: 10.1093/nar/gkaf940
Rezwan Hosseini, Ali Tugrul Balci, Dennis Kostka, Nathan Clark, Maria Chikina
{"title":"Ultra-fast variant effect prediction using biophysical transcription factor binding models","authors":"Rezwan Hosseini, Ali Tugrul Balci, Dennis Kostka, Nathan Clark, Maria Chikina","doi":"10.1093/nar/gkaf940","DOIUrl":"https://doi.org/10.1093/nar/gkaf940","url":null,"abstract":"Sequence variation within transcription factor (TF)-binding sites can significantly affect TF–DNA interactions, influencing gene expression and contributing to disease susceptibility or phenotypic traits. Despite recent progress in deep sequence-to-function models that predict functional output from sequence data, these methods perform inadequately on some variant effect prediction tasks, especially with common genetic variants. This limitation underscores the importance of leveraging biophysical models of TF binding to enhance interpretability of variant effect scores and facilitate mechanistic insights. We introduce motifDiff, a novel computational tool designed to quantify variant effects using mono- and dinucleotide position weight matrices. motifDiff offers several key advantages, including scalability to score millions of variants within minutes, implementation of statistically rigorous normalization strategy critical for optimal performance, and support for both dinucleotide and mononucleotide models. We demonstrate motifDiff’s efficacy by evaluating it across diverse ground truth datasets that quantify the effects of common variants in vivo, thereby establishing robust benchmarks for the predictive value of variant effect calculations. Finally, we show that our tool provides unique insights when interpreting human accelerated regions. motifDiff is available as a standalone Python application at https://github.com/rezwanhosseini/MotifDiff.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"82 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
VARIDT 4.0: distribution variability of drug transporters. VARIDT 4.0:药物转运体的分布变异性。
IF 14.9 2区 生物学
Nucleic Acids Research Pub Date : 2025-10-02 DOI: 10.1093/nar/gkaf981
Yinghong Li,Fan Yang,Zupeng Pan,Yudong Yan,Boren Jiang,Xuanhao Huang,Hongyin Wang,Xiang Qin,Jiayi Yin,Su Zeng,Tingting Fu,Feng Zhu
{"title":"VARIDT 4.0: distribution variability of drug transporters.","authors":"Yinghong Li,Fan Yang,Zupeng Pan,Yudong Yan,Boren Jiang,Xuanhao Huang,Hongyin Wang,Xiang Qin,Jiayi Yin,Su Zeng,Tingting Fu,Feng Zhu","doi":"10.1093/nar/gkaf981","DOIUrl":"https://doi.org/10.1093/nar/gkaf981","url":null,"abstract":"The multilevel distribution variability of drug transporters-from tissues to cells and organelles-is critical for understanding drug response, drug-drug interactions, and multidrug resistance. The absorption, dispersion, metabolism, and excretion properties of drugs are codetermined by these multilevel distribution patterns, including tissue-specific expression, cellular heterogeneity, and subcellular localization. However, a public database that systematically integrates these crucial data of drug transporter distribution variability has been lacking. Therefore, in this major update, VARIDT 4.0 was developed to provide a comprehensive resource, incorporating 25 797 tissue-level expression profiles, 451 830 cell-level expression records, and 1034 subcellular localization entries. Additionally, the foundational modules on general, structural, and regulatory variability were extensively updated. This multilevel variability data is highly relevant to the transport of 889 approved and 221 clinical trial drugs, as well as 689 endogenous metabolites, implicated in the treatment of 558 diseases. Furthermore, by integrating these new distribution layers with its existing data, VARIDT 4.0 now enables comprehensive consideration of how a transporter's function is modulated by its specific spatiotemporal context. Overall, VARIDT 4.0 is expected to be a valuable data repository for system pharmacology, serving as an essential complement to existing pharmaceutical databases, and is freely accessible without login at https://idrblab.org/varidt/.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"8 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Systematic identification of regions where DNA methylation is correlated with transcription refines regulatory logic in normal and tumour tissues 系统地识别DNA甲基化与转录相关的区域,可以改善正常组织和肿瘤组织的调控逻辑
IF 14.9 2区 生物学
Nucleic Acids Research Pub Date : 2025-09-30 DOI: 10.1093/nar/gkaf949
Richard Heery, Martin H Schaefer
{"title":"Systematic identification of regions where DNA methylation is correlated with transcription refines regulatory logic in normal and tumour tissues","authors":"Richard Heery, Martin H Schaefer","doi":"10.1093/nar/gkaf949","DOIUrl":"https://doi.org/10.1093/nar/gkaf949","url":null,"abstract":"DNA methylation at gene promoters is generally considered to be associated with transcriptional repression in vertebrates. However, lack of a clear picture of where promoter methylation is most important for transcriptional regulation has hindered our understanding of this relationship and resulted in the use of a wide variety of arbitrary promoter definitions. We demonstrate here that the use of different promoter definitions can lead to contradictory results between studies of promoter methylation. In response, we have developed Methodical, a computational method that combines RNA-seq and whole genome bisulfite sequencing (WGBS) data to identify genomic regions where DNA methylation is highly correlated with transcriptional activity. We refer to these regions as transcript-proximal methylation-associated regulatory sites (TMRs). We applied Methodical to one normal prostate tissue data set, one prostate tumour dataset, and one prostate metastasis dataset and characterized the identified TMRs. We show that the region just downstream of the TSS is the most common location for TMRs and that TMRs are enriched for particular genomic features, chromatin states, and transcription factor binding sites. Finally, we demonstrate that the methylation of TMRs is generally strongly correlated with transcription in diverse cancer types and that TMRs are highly subject to altered DNA methylation in cancer.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"31 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145188780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Leading and lagging strand abasic sites differentially affect vertebrate replisome progression but involve analogous bypass mechanisms 前导链和后链基本位点对脊椎动物复制体进展的影响不同,但涉及类似的旁路机制
IF 14.9 2区 生物学
Nucleic Acids Research Pub Date : 2025-09-30 DOI: 10.1093/nar/gkaf975
Matthew T Cranford, Steven N Dahmen, David Cortez, James M Dewar
{"title":"Leading and lagging strand abasic sites differentially affect vertebrate replisome progression but involve analogous bypass mechanisms","authors":"Matthew T Cranford, Steven N Dahmen, David Cortez, James M Dewar","doi":"10.1093/nar/gkaf975","DOIUrl":"https://doi.org/10.1093/nar/gkaf975","url":null,"abstract":"Abasic sites are frequent DNA lesions that interfere with replication and exert complex biological effects because they can be processed into other lesions. Thus, it remains poorly understood how abasic sites affect replisome progression, which repair pathways they elicit, and whether this depends on the template strand damaged. Using Xenopus egg extracts, we developed an approach to analyze replication of DNA containing a site-specific, stable abasic site on the leading or lagging strand template. We show that abasic sites robustly stall DNA synthesis but exert strand-specific effects. Leading strand abasic sites stall leading strands at the lesion, while lagging strands stall downstream at template-dependent positions. We conclude that replisomes uncouple at leading strand lesions, then stall due to additional template constraints. Synthesis restarts upon lesion bypass or when a converging fork triggers termination. In contrast, lagging strand abasic sites stall only lagging strands, indicating replisome progression was unaffected. Lagging strands reprime downstream, generating a post-replicative gap that is subsequently filled. Despite different effects on replisome progression, both leading and lagging strand abasic sites require translesion DNA synthesis for bypass. Our results reveal how strand-specific abasic sites differentially affect replication and demonstrate that uncoupled replisomes are susceptible to downstream template constraints.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"1 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145188689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
WDR5 serves in co-activation and influences genome targeting of KLF3 WDR5参与共激活并影响KLF3的基因组靶向性
IF 14.9 2区 生物学
Nucleic Acids Research Pub Date : 2025-09-30 DOI: 10.1093/nar/gkaf977
Lu Yang, Manan Shah, Tanit Chavalit, Annalise M Spek, Wooi F Lim, Ling Zhong, Vala Nejad Safari, Mahdi Haddad, Thu H Vu, Joel P Mackay, Mark J Raftery, Marc R Wilkins, Jacqueline M Mathews, Kate G R Quinlan, Merlin Crossley
{"title":"WDR5 serves in co-activation and influences genome targeting of KLF3","authors":"Lu Yang, Manan Shah, Tanit Chavalit, Annalise M Spek, Wooi F Lim, Ling Zhong, Vala Nejad Safari, Mahdi Haddad, Thu H Vu, Joel P Mackay, Mark J Raftery, Marc R Wilkins, Jacqueline M Mathews, Kate G R Quinlan, Merlin Crossley","doi":"10.1093/nar/gkaf977","DOIUrl":"https://doi.org/10.1093/nar/gkaf977","url":null,"abstract":"Krüppel-like factor 3 (KLF3) is a member of the archetypal SP/KLF family of transcription factors that bind GC-rich elements and CACCC boxes in promoters and enhancers via three classical zinc fingers (ZFs) at or near their C-termini. KLF3 can both repress and activate transcription. It represses by recruiting CtBP co-repressors via its N-terminal domain but the mechanism by which it activates was unknown. Here, we show that KLF3 associates with WDR5 and this interaction is associated with gene activation. We also demonstrate that this interaction is required for proper genomic targeting of KLF3. This helps explain previous results indicating that both the C-terminal ZF DNA-binding domain and N-terminal functional domain are required for KLF3 to identify its target genes. This result adds to only a handful of examples that transcriptional co-regulators, in addition to facilitating activation and repression, can also influence target gene selection.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"113 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145195155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Mechanistic insights into Cas13d enzymes from cryo-EM structures of CasRx and DjCas13d 从CasRx和DjCas13d的低温电镜结构研究Cas13d酶的机制
IF 14.9 2区 生物学
Nucleic Acids Research Pub Date : 2025-09-30 DOI: 10.1093/nar/gkaf986
Xiaoyan Chen, Yongru He, Maochao Guo, Shiyu Liu, Yue Li, Fuxing Zeng, Chongyuan Wang, Kai Yuan, Hongda Huang
{"title":"Mechanistic insights into Cas13d enzymes from cryo-EM structures of CasRx and DjCas13d","authors":"Xiaoyan Chen, Yongru He, Maochao Guo, Shiyu Liu, Yue Li, Fuxing Zeng, Chongyuan Wang, Kai Yuan, Hongda Huang","doi":"10.1093/nar/gkaf986","DOIUrl":"https://doi.org/10.1093/nar/gkaf986","url":null,"abstract":"CasRx and its engineered variants have emerged as powerful RNA-targeting tools, exhibiting high specificity, robust efficiency, and minimal trans-cleavage activity. Recently, DjCas13d was identified as a promising alternative, offering even lower trans-cleavage activity while retaining comparable cis-cleavage efficiency. Despite their broad utility in biotechnology and therapeutic development, the molecular mechanisms governing substrate recognition and activation in these functionally relevant Cas13d enzymes remain incompletely understood. Here, we present comparative structural and biochemical analyses of CasRx and DjCas13d. Using cryogenic electron microscopy, we determined structures of both enzymes in binary (protein–crRNA) and ternary (protein–crRNA–target RNA) states, and additionally solved the apo structure of DjCas13d. Biochemical assays revealed that both enzymes exhibit similar cis-cleavage activity, whereas DjCas13d shows substantially reduced trans-cleavage activity relative to CasRx. Structural comparisons uncovered key conformational changes linked to target RNA engagement and catalytic activation, providing mechanistic insight into their distinct cleavage behaviors. Furthermore, structure-guided mutagenesis yielded several CasRx variants that achieve a favorable balance between reduced trans-cleavage activity and preserved cis-cleavage efficiency, representing valuable starting points for further optimization. Together, these findings advance our mechanistic understanding of Cas13 enzymes and provide a structural framework for the rational design of RNA-targeting technologies.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"19 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145188779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Iron-sensitive RNA regulation by poly C-binding proteins 聚c结合蛋白对铁敏感RNA的调控
IF 14.9 2区 生物学
Nucleic Acids Research Pub Date : 2025-09-30 DOI: 10.1093/nar/gkaf942
Grant A Goda, Kwame Forbes, Michael E Sullivan, Grace A Eramo, Conner Breen, Douglas F Porter, Paul A Khavari, Daniel Dominguez, Maria M Aleman
{"title":"Iron-sensitive RNA regulation by poly C-binding proteins","authors":"Grant A Goda, Kwame Forbes, Michael E Sullivan, Grace A Eramo, Conner Breen, Douglas F Porter, Paul A Khavari, Daniel Dominguez, Maria M Aleman","doi":"10.1093/nar/gkaf942","DOIUrl":"https://doi.org/10.1093/nar/gkaf942","url":null,"abstract":"Iron is essential for normal cellular function. Homeostatic responses to low iron availability have long been known to rely on posttranscriptional mechanisms. Poly C-binding proteins (PCBPs) are essential RNA-binding proteins that regulate alternative splicing (AS), translation, and RNA stability. They also serve as critical iron chaperones that manage intracellular iron flux. However, the impact of cellular iron levels on the PCBP-directed transcriptome has not been globally evaluated. We found broad transcriptome changes, including AS, in response to low iron availability consistent with numerous operant posttranscriptional mechanisms that sense iron. By comparing AS directed by PCBP1 and PCBP2 to the iron-sensitive transcriptome, we found genes with iron-sensitive PCBP-mediated splicing regulation. We also found that iron chelation-induced splicing changes were attenuated with knockdown of PCBPs. Further, we demonstrate that iron chelation or mutation of PCBP1 iron binding residues enhances PCBP1 RNA association. This work highlights widespread iron-sensitive RNA regulation and identifies PCBP1 and PCBP2 as critical splicing factors contributing to this response.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"95 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145188693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Gene4Denovo2: an updated platform for human de novo mutations discovery and interpretation Gene4Denovo2:人类新生突变发现和解释的更新平台
IF 14.9 2区 生物学
Nucleic Acids Research Pub Date : 2025-09-30 DOI: 10.1093/nar/gkaf980
Zhaopo Zhu, Pei Yu, Xinxin Mao, Chenbin Liu, Kuokuo Li, Qiao Zhou, Yijing Wang, Tengfei Luo, Xudong Xiang, Yixiao Zhu, Dai Wu, Xingxing Jian, Bin Li, Beisha Tang, Kun Xia, Guihu Zhao, Jinchen Li
{"title":"Gene4Denovo2: an updated platform for human de novo mutations discovery and interpretation","authors":"Zhaopo Zhu, Pei Yu, Xinxin Mao, Chenbin Liu, Kuokuo Li, Qiao Zhou, Yijing Wang, Tengfei Luo, Xudong Xiang, Yixiao Zhu, Dai Wu, Xingxing Jian, Bin Li, Beisha Tang, Kun Xia, Guihu Zhao, Jinchen Li","doi":"10.1093/nar/gkaf980","DOIUrl":"https://doi.org/10.1093/nar/gkaf980","url":null,"abstract":"De novo mutations (DNMs) drive evolution and increase biodiversity, yet concurrently act as a cryptic cause of numerous genetic diseases. Here, we present Gene4Denovo2 (https://genemed.tech/gene4denovo2/), an updated version of the Gene4Denovo, aiming to provide a more comprehensive DNM datasets and their interpretations. The key improvements include the following: (i) We have substantially expanded the number and scope of DNMs, associated samples, and phenotypes. Specifically, Gene4Denovo2 now contains 1 626 050 DNMs from 130 439 individuals across 96 phenotypes. Moreover, clinical information covering nearly 1000 items has been added for 448 096 individuals, including those with DNMs and their unaffected family members. (ii) We have introduced new features to assist in the evaluation of DNMs, including support for ACMG rating and the addition of gene prioritization scores for rapid classification and filtering of candidate genes. (iii) An upgraded analysis interface allowing flexible annotation configuration and a significant expansion in the number of annotatable datasets. Additionally, a new integrated tool enables DNMs calling from family-based sequencing data. In summary, Gene4Denovo2 provides a more extensive collection of DNMs, enhanced annotation capabilities, and upgraded analysis tools, which will facilitate a deeper exploration of the role of DNMs in disease pathogenesis.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"70 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145188781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
CRESTA: a comprehensive transcriptome atlas for cellular response to external stressors CRESTA:细胞对外部应激源反应的综合转录组图谱
IF 14.9 2区 生物学
Nucleic Acids Research Pub Date : 2025-09-30 DOI: 10.1093/nar/gkaf968
Hongge Wang, Weiping Mu, Xiaoqiong Bao, Luowanyue Zhang, Yuxi Xie, Huiqin Li, Kebing Wang, Yaqing Cao, Jingsong Chen, Jikai Zhan, Lingxiao Li, Jun Shen, Jian Ren, Zhixiang Zuo
{"title":"CRESTA: a comprehensive transcriptome atlas for cellular response to external stressors","authors":"Hongge Wang, Weiping Mu, Xiaoqiong Bao, Luowanyue Zhang, Yuxi Xie, Huiqin Li, Kebing Wang, Yaqing Cao, Jingsong Chen, Jikai Zhan, Lingxiao Li, Jun Shen, Jian Ren, Zhixiang Zuo","doi":"10.1093/nar/gkaf968","DOIUrl":"https://doi.org/10.1093/nar/gkaf968","url":null,"abstract":"Cellular stress response (CSR) is crucial for maintaining intracellular homeostasis upon exposure to hazardous environmental stressors, whose failure can lead to cell death. Here, we developed CRESTA (https://cresta.renlab.cn/), an integrated database providing a comprehensive resource for studying stressor-induced CSR. CRESTA unifies fragmented transcriptomic data across diverse stressors, cell types, and contexts into a hierarchically structured atlas. It catalogs 20 786 unique stress-associated genes responding to 14 major categories (180 sub-categories) of human cellular stressors, based on the differential expression analysis of 8258 samples spanning 197 human cell types. These stressor categories include air pollutants, antineoplastic agents, heavy metals, hypoxia, mechanical stimuli, natural toxins, nutrient deprivation, pesticides, radiation, temperature change, etc. To further enable causal inference between stressors and molecular pathologies, CRESTA links CSR transcriptomic signatures to functional pathways, cell death annotations, and disease associations. Additionally, the CSR profiles are connected with chemical perturbation features involving FDA-approved drugs to support systematic drug repurposing. Overall, we expect that CRESTA will serve as a vital resource for mechanistic studies of cytotoxicity, cellular perturbation evaluation, and CSR-targeted drug discovery.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"5 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145188778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
ARID1A regulates histone octamer transfer activity of human canonical BAF complex ARID1A调节人典型BAF复合物的组蛋白八聚体转移活性
IF 14.9 2区 生物学
Nucleic Acids Research Pub Date : 2025-09-29 DOI: 10.1093/nar/gkaf958
Naoe Moro, Yukiko Fujisawa-Tanaka, Shinya Watanabe
{"title":"ARID1A regulates histone octamer transfer activity of human canonical BAF complex","authors":"Naoe Moro, Yukiko Fujisawa-Tanaka, Shinya Watanabe","doi":"10.1093/nar/gkaf958","DOIUrl":"https://doi.org/10.1093/nar/gkaf958","url":null,"abstract":"Mutations that impact subunits of mammalian SWI/SNF (mSWI/SNF or BAF) chromatin remodeling complexes are found in over 20% of human cancers. Among these subunits, AT-rich interactive domain-containing protein 1A (ARID1A) is the most frequently mutated gene, occurring in over 8% of various cancers. The majority of ARID1A mutations are frameshift or nonsense mutations, causing loss of function. Previous studies have suggested that ARID1A may facilitate interactions between BAF complexes and various transcriptional coactivators, but a biochemical role for ARID1A in BAF remodeling activity has not been identified. Here, we describe the in vitro reconstitution of the cBAF, PBAF, and ncBAF complexes, and we compare their biochemical activities. In addition, we reconstitute a variety of cBAF subcomplexes, defining roles for several subunits in high affinity nucleosome binding and nucleosome sliding activity. Remarkably, we find that the ARID1A subunit of cBAF is largely dispensable for nucleosome binding, nucleosome sliding, and adenosine triphosphatase activity, but ARID1A is required for cBAF to transfer histone octamers between DNA templates. Our study reveals a biochemical function of ARID1A/ARID1B in BAF-mediated chromatin remodeling, suggesting a model in which dysregulation of histone octamer transfer activity of BAF complexes may be relevant to cancer formation.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"19 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
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