Biochimica et Biophysica Acta-Gene Regulatory Mechanisms最新文献

{"title":"The presence of an intron relieves gene repression caused by promoter-proximal four-bp specific sequences in yeast","authors":"Hiroki Kikuta ,&nbsp;Takahiro Aramaki ,&nbsp;Shingo Mabu ,&nbsp;Rinji Akada ,&nbsp;Hisashi Hoshida","doi":"10.1016/j.bbagrm.2023.194982","DOIUrl":"10.1016/j.bbagrm.2023.194982","url":null,"abstract":"<div><p>Introns can enhance gene expression in eukaryotic cells in a process called intron-mediated enhancement (IME). The levels of enhancement are affected not only by the intron sequence but also by coding sequences (CDSs). However, the parts of CDSs responsible for mediating IME have not yet been identified. In this study, we identified an IME-mediating sequence by analyzing three pairs of IME-sensitive and -insensitive CDSs in <span><em>Saccharomyces cerevisiae</em></span>. Expression of the CDSs y<em>CLuc</em>, yRo<em>GLU1</em>, and Km<em>BGA1</em><span> was enhanced by the presence of an intron (i.e., they were IME sensitive), but the expression of each corresponding codon-changed CDS, which encoded the identical amino acid sequence, was not enhanced (i.e., they were IME insensitive). Interestingly, the IME-insensitive CDSs showed higher expression levels that were like intron-enhanced expression of IME-sensitive CDSs, suggesting that expression of IME-sensitive CDSs was repressed. A four-nucleotide sequence (TCTT) located in the promoter-proximal position of either the untranslated or coding region was found to be responsible for repression in IME-sensitive CDSs, and repression caused by the TCTT sequence was relieved by the presence of an intron. Further, it was found that the expression of intron-containing yeast-native genes, </span><em>UBC4</em> and <em>MPT5</em><span>, was repressed by TCTT in the CDS but relieved by the introns. These results indicate that TCTT sequences in promoter-proximal positions repress gene expression and that introns play a role in relieving gene repression caused by sequences such as TCTT.</span></p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 4","pages":"Article 194982"},"PeriodicalIF":4.7,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10194516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fine tuning of the transcription juggernaut: A sweet and sour saga of acetylation and ubiquitination","authors":"Avik Ghosh ,&nbsp;Poushali Chakraborty ,&nbsp;Debabrata Biswas","doi":"10.1016/j.bbagrm.2023.194944","DOIUrl":"10.1016/j.bbagrm.2023.194944","url":null,"abstract":"<div><p><span>Among post-translational modifications of proteins, acetylation, phosphorylation, and ubiquitination are most extensively studied over the last several decades. Owing to their different target residues for modifications, cross-talk between phosphorylation with that of acetylation and ubiquitination is relatively less pronounced. However, since canonical acetylation and ubiquitination happen only on the lysine residues, an overlap of the same lysine residue being targeted for both acetylation and ubiquitination happens quite frequently and thus plays key roles in overall functional regulation predominantly through modulation of protein stability. In this review, we discuss the cross-talk of acetylation and ubiquitination in the regulation of protein stability for the functional regulation of cellular processes with an emphasis on transcriptional regulation. Further, we emphasize our understanding of the functional regulation of Super Elongation Complex (SEC)-mediated transcription, through regulation of stabilization by acetylation, </span>deacetylation<span> and ubiquitination and associated enzymes and its implication in human diseases.</span></p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 3","pages":"Article 194944"},"PeriodicalIF":4.7,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10392911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crystal structure of Tudor domain of TDRD3 in complex with a small molecule antagonist","authors":"Meixia Chen ,&nbsp;Zhuowen Wang ,&nbsp;Weiguo Li ,&nbsp;Yichang Chen ,&nbsp;Qin Xiao ,&nbsp;Xinci Shang ,&nbsp;Xiaolei Huang ,&nbsp;Zhengguo Wei ,&nbsp;Xinyue Ji ,&nbsp;Yanli Liu","doi":"10.1016/j.bbagrm.2023.194962","DOIUrl":"10.1016/j.bbagrm.2023.194962","url":null,"abstract":"<div><p><span><span>Tudor domain-containing protein 3 (TDRD3) is involved in regulating transcription and translation, promoting breast cancer progression, and modulating neurodevelopment and mental health, making it a promising therapeutic target for associated diseases. The </span>Tudor domain of TDRD3 is essential for its biological functions, and targeting this domain with potent and selective chemical probes may modulate its engagement with chromatin and related functions. Here we reported a study of TDRD3 antagonist following on our earlier work on the development of the SMN antagonist, Compound </span><strong>1</strong>, and demonstrated that TDRD3 can bind effectively to Compound <strong>2</strong>, a triple-ring analog of Compound <strong>1</strong>. Our structural analysis suggested that the triple-ring compound bound better to TDRD3 due to its smaller side chain at Y566 compared to W102 in SMN. We also revealed that adding a small hydrophobic group to the <em>N</em>-methyl site of Compound <strong>1</strong> can improve binding. These findings provide a path for identifying antagonists for single canonical Tudor domain-containing proteins such as TDRD3 and SMN.</p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 3","pages":"Article 194962"},"PeriodicalIF":4.7,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10412495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"UPS writes a new saga of SAGA","authors":"Priyanka Barman,&nbsp;Pritam Chakraborty,&nbsp;Rhea Bhaumik,&nbsp;Sukesh R. Bhaumik","doi":"10.1016/j.bbagrm.2023.194981","DOIUrl":"10.1016/j.bbagrm.2023.194981","url":null,"abstract":"<div><p>SAGA (<u>S</u>pt-<u>A</u>da-<u>G</u>cn5-<u>A</u><span><span>cetyltransferase), an evolutionarily conserved transcriptional co-activator among eukaryotes, is a large multi-subunit protein complex with two distinct </span>enzymatic activities, namely HAT (</span><u>H</u>istone <u>a</u>cetyl<u>t</u>ransferase) and DUB (<u>D</u>e-<u>ub</u><span>iquitinase), and is targeted to the promoter by the gene-specific activator proteins for histone covalent modifications and PIC (</span><u>P</u>re-<u>i</u>nitiation <u>c</u>omplex) formation in enhancing transcription (or gene activation). Targeting of SAGA to the gene promoter is further facilitated by the 19S RP (<u>R</u>egulatory <u>p</u><span>article) of the 26S proteasome<span> (that is involved in targeted degradation of protein via ubiquitylation) in a proteolysis-independent manner. Moreover, SAGA is also recently found to be regulated by the 26S proteasome in a proteolysis-dependent manner via the ubiquitylation of its Sgf73/ataxin-7 component that is required for SAGA's integrity and DUB activity (and hence transcription), and is linked to various diseases including neurodegenerative disorders and cancer. Thus, SAGA itself and its targeting to the active gene are regulated by the UPS (</span></span><u>U</u>biquitin-<u>p</u>roteasome <u>s</u>ystem) with implications in diseases.</p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 4","pages":"Article 194981"},"PeriodicalIF":4.7,"publicationDate":"2023-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10261368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of clusterin gene 3’-UTR polymorphisms and promoter hypomethylation in the pathogenesis of pseudoexfoliation syndrome and pseudoexfoliation glaucoma","authors":"Ramani Shyam Kapuganti ,&nbsp;Lipsa Sahoo ,&nbsp;Pranjya Paramita Mohanty ,&nbsp;Bushra Hayat ,&nbsp;Sucheta Parija ,&nbsp;Debasmita Pankaj Alone","doi":"10.1016/j.bbagrm.2023.194980","DOIUrl":"10.1016/j.bbagrm.2023.194980","url":null,"abstract":"<div><p><span><span>Pseudoexfoliation (PEX) is a multifactorial age-related disease characterized by the deposition of extracellular fibrillar aggregates in the anterior ocular tissues. This study aims to identify the genetic<span> and epigenetic contribution of </span></span>clusterin<span> (CLU) in PEX pathology. CLU is a molecular chaperone upregulated in PEX and genetically associated with the disease. Sequencing of a 2.9 kb region encompassing the previously associated rs2279590 in 250 control and 313 PEX [(207 pseudoexfoliation syndrome (PEXS) and 106 pseudoexfoliation glaucoma (PEXG)] individuals identified three single nucleotide polymorphisms (SNPs), rs9331942, rs9331949 and rs9331950, in the 3’-UTR of </span></span><em>CLU</em><span> of which rs9331942 and rs9331949 were found to be significantly associated with PEXS and PEXG as risk factors. Following in silico analysis, in vitro luciferase<span> reporter assays in human embryonic kidney cells revealed that risk alleles at rs9331942 and rs9331949 bind to miR-223 and miR-1283, respectively, suggesting differential regulation of clusterin in the presence of risk alleles at the SNPs. Further, through bisulfite sequencing, we also identified that </span></span><em>CLU</em><span><span> promoter is hypomethylated in DNA from blood and lens capsules of PEX patients compared to controls that correlated with decreased expression of </span>DNA methyltransferase<span> 1 (DNMT1). Promoter demethylation of </span></span><em>CLU</em> using DNMT inhibitor, 5′-aza-dC, in human lens epithelial cells increased CLU expression. Chromatin immunoprecipitation assays showed that the demethylated <em>CLU</em> promoter provides increased access to the transcription factor, Sp1, which might lead to enhanced expression of CLU. In conclusion, this study highlights the different molecular mechanisms of clusterin regulation in pseudoexfoliation pathology.</p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 4","pages":"Article 194980"},"PeriodicalIF":4.7,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10235128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The versatility of the proteasome in gene expression and silencing: Unraveling proteolytic and non-proteolytic functions","authors":"Hyesu Lee ,&nbsp;Sungwook Kim ,&nbsp;Daeyoup Lee","doi":"10.1016/j.bbagrm.2023.194978","DOIUrl":"10.1016/j.bbagrm.2023.194978","url":null,"abstract":"<div><p><span>The 26S proteasome consists of a 20S core particle and a 19S regulatory particle and critically regulates gene expression and silencing through both proteolytic and non-proteolytic functions. The 20S core particle mediates </span>proteolysis<span><span>, while the 19S regulatory particle performs non-proteolytic functions. The proteasome plays a role in regulating gene expression in euchromatin<span> by modifying histones, activating transcription, initiating and terminating transcription, mRNA export, and maintaining </span></span>transcriptome<span><span> integrity. In gene silencing, the proteasome modulates the heterochromatin formation, spreading, and </span>subtelomere silencing by degrading specific proteins and interacting with anti-silencing factors such as Epe1, Mst2, and Leo1. This review discusses the proteolytic and non-proteolytic functions of the proteasome in regulating gene expression and gene silencing-related heterochromatin formation. This article is part of a special issue on the regulation of gene expression and genome integrity by the ubiquitin-proteasome system.</span></span></p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 4","pages":"Article 194978"},"PeriodicalIF":4.7,"publicationDate":"2023-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10118733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ubiquitination and deubiquitination: Implications on cancer therapy","authors":"Gunjan Dagar ,&nbsp;Rakesh Kumar ,&nbsp;Kamlesh K. Yadav ,&nbsp;Mayank Singh ,&nbsp;Tej K. Pandita","doi":"10.1016/j.bbagrm.2023.194979","DOIUrl":"10.1016/j.bbagrm.2023.194979","url":null,"abstract":"<div><p>The ubiquitin proteasomal system (UPS) represents a highly regulated protein degradation<span><span><span> pathway essential for maintaining cellular homeostasis. This system plays a critical role in several cellular processes, which include DNA damage repair, </span>cell cycle checkpoint control, and immune response regulation. Recently, the UPS has emerged as a promising target for cancer therapeutics due to its involvement in oncogenesis and tumor progression. Here we aim to summarize the key aspects of the UPS and its significance in cancer therapeutics. We begin by elucidating the fundamental components of the UPS, highlighting the role of ubiquitin, E1-E3 </span>ligases<span><span>, and the proteasome<span> in protein degradation. Furthermore, we discuss the intricate process of ubiquitination and proteasomal degradation, emphasizing the specificity and selectivity achieved through various </span></span>signaling pathways<span><span>. The dysregulation of the UPS has been implicated in cancer development and progression. Aberrant ubiquitin-mediated degradation of key regulatory proteins, such as tumor suppressors and oncoproteins, can lead to uncontrolled </span>cell proliferation<span><span>, evasion of apoptosis, and metastasis. We outline the pivotal role of the UPS in modulating crucial oncogenic pathways, including the regulation of cyclins, transcription factors, Replication stress components and DNA damage response. The increasing recognition of the UPS as a target for cancer therapeutics has spurred the development of </span>small molecules<span>, peptides, and proteasome inhibitors<span> with the potential to restore cellular balance and disrupt tumor growth. We provide an overview of current therapeutic strategies aimed at exploiting the UPS, including the use of proteasome inhibitors, deubiquitinating enzyme inhibitors, and novel E3 ligase modulators. We further discuss novel emerging strategies for the development of next-generation drugs that target proteasome inhibitors. Exploiting the UPS for cancer therapeutics offers promising avenues for developing innovative and effective treatment strategies, providing hope for improved patient outcomes in the fight against cancer.</span></span></span></span></span></span></p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 4","pages":"Article 194979"},"PeriodicalIF":4.7,"publicationDate":"2023-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10142364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein post-translational modifications: A key factor in colorectal cancer resistance mechanisms","authors":"Bo Bi ,&nbsp;Miaojuan Qiu ,&nbsp;Peng Liu ,&nbsp;Qiang Wang ,&nbsp;Yingfei Wen ,&nbsp;You Li ,&nbsp;Binbin Li ,&nbsp;Yongshu Li ,&nbsp;Yulong He ,&nbsp;Jing Zhao","doi":"10.1016/j.bbagrm.2023.194977","DOIUrl":"10.1016/j.bbagrm.2023.194977","url":null,"abstract":"<div><p>Colorectal cancer (CRC) is one of the leading causes of cancer-related death. Despite advances in treatment, drug resistance remains a critical impediment. Post-translational modifications (PTMs) regulate protein stability, localization, and activity, impacting vital cellular processes. Recent research has highlighted the essential role of PTMs in the development of CRC resistance. This review summarizes recent advancements in understanding PTMs' roles in CRC resistance, focusing on the latest discoveries. We discuss the functional impact of PTMs on signaling pathways and molecules involved in CRC resistance, progress in drug development, and potential therapeutic targets. We also summarize the primary enrichment methods for PTMs. Finally, we discuss current challenges and future directions, including the need for more comprehensive PTM analysis methods and PTM-targeted therapies. This review identifies potential therapeutic interventions for addressing medication resistance in CRC, proposes prospective therapeutic options, and gives an overview of the function of PTMs in CRC resistance.</p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 4","pages":"Article 194977"},"PeriodicalIF":4.7,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10494009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Post-translational modifications of lysine-specific demethylase 1","authors":"Dongha Kim ,&nbsp;Hye Jin Nam ,&nbsp;Sung Hee Baek","doi":"10.1016/j.bbagrm.2023.194968","DOIUrl":"10.1016/j.bbagrm.2023.194968","url":null,"abstract":"<div><p>Lysine-specific demethylase 1 (LSD1) is crucial for regulating gene expression by catalyzing the demethylation of mono- and di-methylated histone H3 lysine 4 (H3K4) and lysine 9 (H3K9) and non-histone proteins through the amine oxidase activity with FAD⁺ as a cofactor. It interacts with several protein partners, which potentially contributes to its diverse substrate specificity. Given its pivotal role in numerous physiological and pathological conditions, the function of LSD1 is closely regulated by diverse post-translational modifications (PTMs), including phosphorylation, ubiquitination, methylation, and acetylation. In this review, we aim to provide a comprehensive understanding of the regulation and function of LSD1 following various PTMs. Specifically, we will focus on the impact of PTMs on LSD1 function in physiological and pathological contexts and discuss the potential therapeutic implications of targeting these modifications for the treatment of human diseases.</p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 4","pages":"Article 194968"},"PeriodicalIF":4.7,"publicationDate":"2023-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10082073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N6-methyladenosine (m6A) methylation in kidney diseases: Mechanisms and therapeutic potential","authors":"Yuting Sun ,&nbsp;De Jin ,&nbsp;Ziwei Zhang ,&nbsp;Hangyu Ji ,&nbsp;Xuedong An ,&nbsp;Yuehong Zhang ,&nbsp;Cunqing Yang ,&nbsp;Wenjie Sun ,&nbsp;Yuqing Zhang ,&nbsp;Yingying Duan ,&nbsp;Xiaomin Kang ,&nbsp;Linlin Jiang ,&nbsp;Xuefei Zhao ,&nbsp;Fengmei Lian","doi":"10.1016/j.bbagrm.2023.194967","DOIUrl":"10.1016/j.bbagrm.2023.194967","url":null,"abstract":"<div><p>The N6-methyladenosine (m6A) modification is regulated by methylases, commonly referred to as “writers,” and demethylases, known as “erasers,” leading to a dynamic and reversible process. Changes in m6A levels have been implicated in a wide range of cellular processes, including nuclear RNA export, mRNA metabolism, protein translation, and RNA splicing, establishing a strong correlation with various diseases. Both physiologically and pathologically, m6A methylation plays a critical role in the initiation and progression of kidney disease. The methylation of m6A may also facilitate the early diagnosis and treatment of kidney diseases, according to accumulating research. This review aims to provide a comprehensive overview of the potential role and mechanism of m6A methylation in kidney diseases, as well as its potential application in the treatment of such diseases. There will be a thorough examination of m6A methylation mechanisms, paying particular attention to the interplay between m6A writers, m6A erasers, and m6A readers. Furthermore, this paper will elucidate the interplay between various kidney diseases and m6A methylation, summarize the expression patterns of m6A in pathological kidney tissues, and discuss the potential therapeutic benefits of targeting m6A in the context of kidney diseases.</p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 4","pages":"Article 194967"},"PeriodicalIF":4.7,"publicationDate":"2023-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9993758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}