Neena George , Rayzel Fernandes , Kapaettu Satyamoorthy
{"title":"ARID1A-driven modulation of EZH2 impedes proliferation and enhances senescence in breast cancer cells","authors":"Neena George , Rayzel Fernandes , Kapaettu Satyamoorthy","doi":"10.1016/j.bbagrm.2025.195102","DOIUrl":"10.1016/j.bbagrm.2025.195102","url":null,"abstract":"<div><div>ARID1A mutations, in association with EZH2 overexpression, are linked to various malignancies, particularly those driven by epigenetic dysregulation and associated with therapy resistance. The prevalence of ARID1A mutations is high in ER+ breast cancer, and studies have mainly explored the synthetic lethal effects of these proteins. However, the tumor-suppressive mechanisms of ARID1A are complex and not yet fully understood. In this study, we explored the potential tumor-specific epigenetic antagonism between ARID1A and EZH2 in breast cancer cells, particularly focusing on the modulation of EZH2 by ARID1A through senescence pathway activation. Treatment with DNA-damaging agents induced senescence, which was associated with upregulation of ARID1A expression and a concurrent reduction in EZH2 levels, suggesting a potential role for ARID1A in the induction and maintenance of the senescence phenotype. Overexpression of ARID1A led to reduced EZH2 levels, suppressed cell proliferation in MCF-7 and MDA-MB231 cells, and induced a senescence-like phenotype. These cells exhibited changes in cell-to-cell adhesion, increased filopodium formation, and G0/G1 cell cycle arrest. This antiproliferative effect of ARID1A is mediated through the activation of the p53-p21/p16 axis. Furthermore, ARID1A knockdown-associated downregulation of EZH2 highlights the integral role of ARID1A in destabilizing the expression of EZH2 and contributing to cell cycle arrest. Importantly, we found that dasatinib treatment selectively targeted tumor cells overexpressing ARID1A. These findings provide preliminary insight into the molecular mechanisms by which ARID1A regulates EZH2 and establishes a senescence phenotype, offering valuable directions for developing more effective and personalized treatments.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 3","pages":"Article 195102"},"PeriodicalIF":2.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340618","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}
A.I. Garrido-Godino , R. González , M. Martín-Expósito , S. Chávez , J.E. Pérez-Ortín , F. Navarro
{"title":"Growth rate is related to elongation of RNA polymerase II transcription in Saccharomyces cerevisiae","authors":"A.I. Garrido-Godino , R. González , M. Martín-Expósito , S. Chávez , J.E. Pérez-Ortín , F. Navarro","doi":"10.1016/j.bbagrm.2025.195100","DOIUrl":"10.1016/j.bbagrm.2025.195100","url":null,"abstract":"<div><div>Cells must adapt to changing environmental conditions to maintain their fitness and to compete with other genotypes during the natural selection process. The growth rate (GR) is a determining factor in this competition, and it influences gene expression. Some genes increase mRNA levels, while others decrease with the GR. mRNA levels depend on the dynamic balance between their synthesis by RNA polymerase II and their degradation rates. RNA polymerase I and III are also influenced by the GR because they transcribe protein synthesis machinery required to make proteins that increase cell mass during growth. Although RNA levels have been extensively studied in relation to the GR in many organisms, synthesis and degradation rates have, however, been much less investigated. In a previous work, we found a positive correlation between RNA polymerase (RNA pol) II transcription and mRNA degradation with GRs in yeast in batch cultures. Here we extend our study under constant growth conditions in a chemostat and find that overall chromatin-associated RNA pol II levels increase in parallel with the GR. This increase appears to involve the accumulation of partially dephosphorylated RNA pol II with a greater tendency to backtracking, which suggests that the GR modifies the phosphorylation state of RNA pol II at the elongation level. RNA pol I also increases its association with chromatin with the GR, which confirms the general dependence of at least RNA pol I and II transcription on the GR.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 3","pages":"Article 195100"},"PeriodicalIF":2.6,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144267947","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}
Natalia Akulenko , Elena Mikhaleva , Sofya Marfina , Ivan Kutelev , Dmitry Kornyakov , Vlad Bobrov , Andrei Artamonov , Georgij Arapidi , Victoria Shender , Sergei Ryazansky
{"title":"Insights into the target-directed miRNA degradation mechanism in Drosophila ovarian cell culture","authors":"Natalia Akulenko , Elena Mikhaleva , Sofya Marfina , Ivan Kutelev , Dmitry Kornyakov , Vlad Bobrov , Andrei Artamonov , Georgij Arapidi , Victoria Shender , Sergei Ryazansky","doi":"10.1016/j.bbagrm.2025.195092","DOIUrl":"10.1016/j.bbagrm.2025.195092","url":null,"abstract":"<div><div>Target-directed miRNA degradation (TDMD) is a process of post-transcriptional regulation of miRNA stability in animals induced by an extended pairing of Ago-bound miRNAs with specialized complementary RNA targets. As suggested by studies on human cell culture, Ago engaged with the extended duplex is recognized by the ZSWIM8 receptor of the Cullin-RING-ligase complex (CRL3), which also contains Cul3, EloB, and EloC proteins. The CRL activity is accelerated by the neddylation of Cul3 with the involvement of the E2 conjugating protein UbcE2M. The CRL ubiquitinates Ago, resulting in proteolysis of Ago and degradation of the released miRNAs. To date, the molecular mechanism of TDMD has not been studied in other species. To further characterize TDMD in animals, we investigated the protein Dora, the <em>Drosophila</em> ortholog of ZSWIM8, in the culture of <em>Drosophila</em> ovarian somatic cells (OSC). We showed that Dora in OSCs localizes in protein granules unrelated to P- and GW-bodies. The <em>dora</em> knockout resulted in the accumulation of multiple miRNAs, including miR-7-5p, and transcriptome-wide affected the mRNA targets of differentially expressed miRNAs. We also showed that Dora associates with proteins of the CRL3 complex, and the depletion of CRL3 components or inhibition of Cul3 neddylation upregulates miR-7-5p. We concluded that the molecular mechanism of TDMD is conserved in humans and <em>Drosophila</em>. Finally, we found that cells without Dora have an impaired Notch signaling pathway, indicating that TDMD in OSCs may contribute to the modulation of the Notch pathway.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 2","pages":"Article 195092"},"PeriodicalIF":2.6,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143912978","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":"Navigating the tumor landscape: VEGF, MicroRNAs, and the future of cancer treatment","authors":"K.P. Ameya, P.P. Ashikha Shirin Usman, Durairaj Sekar","doi":"10.1016/j.bbagrm.2025.195091","DOIUrl":"10.1016/j.bbagrm.2025.195091","url":null,"abstract":"<div><div>Cancer progression is a multifaceted process influenced by complex interactions within the tumor microenvironment (TME). Central to these dynamics are Vascular Endothelial Growth Factor (VEGF) signalling and microRNA (miRNA) modulation, both of which play critical roles in tumor growth and angiogenesis. VEGF is essential for promoting blood vessel formation; however, its splice variant, VEGF165b, acts as an anti-angiogenic factor, presenting a paradox challenging conventional cancer therapies. Meanwhile, miRNAs regulate gene expression that significantly impacts tumor behaviour by targeting various mRNAs involved in signalling pathways. The interplay between VEGF and miRNAs opens new avenues for targeted therapies designed to disrupt the networks supporting tumor growth. Additionally, the concept of exploiting the unique properties of VEGF splice variants is being explored to develop novel treatments that enhance anti-angiogenic effects while minimizing side effects. Understanding this is crucial for advancing personalized therapies that can effectively address the challenges posed by tumor adaptability and resistance mechanisms.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 2","pages":"Article 195091"},"PeriodicalIF":2.6,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143906728","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}
Yuankang Feng , Jialu Ma , Zhihao Bo , Dan Yue , Yong Wang
{"title":"The crucial role of small heat shock proteins in prostate cancer: mechanisms and new therapeutic perspectives","authors":"Yuankang Feng , Jialu Ma , Zhihao Bo , Dan Yue , Yong Wang","doi":"10.1016/j.bbagrm.2025.195090","DOIUrl":"10.1016/j.bbagrm.2025.195090","url":null,"abstract":"<div><div>As resistance to new anti-androgen drugs occurs more frequently, increasing numbers of researchers are exploring alternative key molecular targets for prostate cancer treatment. The small heat shock protein (sHSP) family is a subclass of heat shock proteins (HSPs). Due to the smaller molecular size of their monomers, they often function as large oligomeric complexes with diverse biological roles, thus garnering increasing attention from urologists. Different members of the sHSP family exhibit distinct biological roles in prostate cancer, offering a new perspective for precision therapy. In this review, we summarize the specific roles of sHSP family members in prostate cancer and analyze their similarities and differences. Additionally, we discuss and review the drugs targeting various sHSPs in prostate cancer, providing new insights into the exploration and further application of sHSP-targeted therapies.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 2","pages":"Article 195090"},"PeriodicalIF":2.6,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143839013","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":"Genome-wide screening reveals repression by nuclear exosome as a prerequisite for intron-mediated enhancement in Saccharomyces cerevisiae","authors":"Hiroki Kikuta , Shunya Takeda , Rinji Akada , Hisashi Hoshida","doi":"10.1016/j.bbagrm.2025.195089","DOIUrl":"10.1016/j.bbagrm.2025.195089","url":null,"abstract":"<div><div>Introns can enhance gene expression, a phenomenon called intron-mediated enhancement (IME). Previously proposed IME mechanisms do not sufficiently explain the variability in enhancement levels, suggesting that IME mechanism has not been fully understood. A comprehensive screening of genes involved in IME can provide valuable insights. Recently, using a luciferase coding sequence (yCLuc), we showed that IME functions by relieving repression rather than simply enhancing expression. The expression of yCLuc is repressed by the specific nucleotide sequence UCUU, and adding an intron relieves this repression in the yeast <em>Saccharomyces cerevisiae</em>. Herein, genome-wide screenings were conducted using <em>S. cerevisiae</em> knockout strain libraries to identify genes involved in IME. For screening, yCLuc was expressed with and without an intron in knockout strains. Consequently, <em>CDC73</em>, a regulator of RNA polymerase II (RNAPII), was identified as essential for enhancement. Additionally, 23 genes specifically involved in the repression were identified. These 23 genes are related to nuclear exosomes, RNA modification, RNAPII regulation, the nuclear pore complex, ribosomes, and chromatin modification. Among these, genes associated with nuclear exosomes, which degrade various RNAs in the nucleus, showed the largest impact on expression. The RNA sequence UCUU has been reported as a target for RNA degradation by nuclear exosomes. These findings suggested that UCUU-containing coding sequences are primarily repressed via RNA degradation by the nuclear exosome through UCUU recognition, with this repression being relieved by the presence of an intron.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 2","pages":"Article 195089"},"PeriodicalIF":2.6,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143851848","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}
Nathan J. Munoff, Brian J. Zeberl, Matthew A. Palmer, Wayne A. Decatur, Bridget M. Walker, Jyoti D. Adala, Zsuzsa K. Szemere, Aula M. Fakhouri, Bruce A. Knutson
{"title":"Specific DNA features of the RNA polymerase I core promoter element targeted by core factor","authors":"Nathan J. Munoff, Brian J. Zeberl, Matthew A. Palmer, Wayne A. Decatur, Bridget M. Walker, Jyoti D. Adala, Zsuzsa K. Szemere, Aula M. Fakhouri, Bruce A. Knutson","doi":"10.1016/j.bbagrm.2025.195088","DOIUrl":"10.1016/j.bbagrm.2025.195088","url":null,"abstract":"<div><div>RNA polymerase I (Pol I) is essential for ribosomal RNA (rRNA) synthesis, driving ribosome biogenesis in eukaryotes. Transcription initiation by Pol I requires core factor (CF) binding to the core element (CE) of the ribosomal DNA (rDNA) promoter. Despite structural conservation across species, significant sequence variability suggests CF recognizes DNA through structural features rather than specific sequences. We investigated CF's DNA binding preferences to elucidate the role of DNA structural properties in CE recognition. Analysis of CE sequences from 35 fungal species revealed conserved structural features, notably a rigid AT-rich patch at positions −22 to −20 and a conserved G base pair at position −24. Competition-based electrophoretic mobility shift assays (EMSA) with single base-pair substitutions showed CF tolerates mutations at many positions but is sensitive to changes in the AT-rich patch. Loss of CF binding correlated with alterations in DNA structural properties such as increased bendability, decreased curvature, widened minor groove width, and altered helix twist. In vitro SELEX experiments identified novel CE sequences preferentially bound by CF, exhibiting increased GC content, higher bendability, and decreased curvature despite lacking sequence conservation. Classification based on bendability profiles revealed CF preferentially binds bendable sequences. In vivo selection assays confirmed these findings, demonstrating consistent CF binding preferences within a cellular context. Our results indicate that CF recognizes and binds to the CE primarily through specific DNA structural features rather than nucleotide sequences. Structural properties like bendability, curvature, and minor groove width are critical determinants of CF binding, facilitating effective Pol I transcription initiation.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 2","pages":"Article 195088"},"PeriodicalIF":2.6,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143843295","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":"Hypoxia inducible factor HIF1α elevates expression of mRNA capping enzyme during cobalt chloride-induced hypoxia","authors":"Safirul Islam, Chandrama Mukherjee","doi":"10.1016/j.bbagrm.2025.195087","DOIUrl":"10.1016/j.bbagrm.2025.195087","url":null,"abstract":"<div><div>In response to hypoxia, hypoxia-inducible factors (HIFs) control the transcriptomic output to mitigate the hypoxic stress. Long noncoding RNAs (lncRNA) are found to be very crucial in regulating hypoxia. Like mRNAs, lncRNAs are protected by 5′ caps that are added by mRNA capping enzyme (CE) in the nucleus. The previous concept that capping takes place in the nucleus was changed by the recognition of a cytoplasmic pool of capping enzyme (cCE). cCE has been shown to recap its substrate uncapped mRNAs or long noncoding RNAs (lncRNAs) present in the cytoplasm, preventing their degradation, even during arsenite-induced oxidative stress. In this study, we examined the effect of CoCl<sub>2</sub> induced hypoxia on cCE and its function in regulating the substrate lncRNAs.</div><div>Here, we show that CoCl<sub>2</sub> induced hypoxia elevates the expressions of nuclear and cytoplasmic CE in HIF1α dependent manner as evidenced by Chromatin immunoprecipitation and HIF1α inhibitor experiments. Furthermore, we found cCE post-transcriptionally controls the stability of its target lncRNAs amidst CoCl<sub>2</sub> induced hypoxia. These results suggest that cCE, upregulated by HIF1α, may act as a posttranscriptional modulator for a few cCE-targeted lncRNAs.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 2","pages":"Article 195087"},"PeriodicalIF":2.6,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143796384","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}
Anna A. Borzykh , Pavel A. Makhnovskii , Ivan I. Ponomarev, Tatiana F. Vepkhvadze, Egor M. Lednev, Ilya V. Rukavishnikov, Oleg I. Orlov, Elena S. Tomilovskaya, Daniil V. Popov
{"title":"Transcription factors associated with regulation of transcriptome in human thigh and calf muscles at baseline and after six days of disuse","authors":"Anna A. Borzykh , Pavel A. Makhnovskii , Ivan I. Ponomarev, Tatiana F. Vepkhvadze, Egor M. Lednev, Ilya V. Rukavishnikov, Oleg I. Orlov, Elena S. Tomilovskaya, Daniil V. Popov","doi":"10.1016/j.bbagrm.2025.195086","DOIUrl":"10.1016/j.bbagrm.2025.195086","url":null,"abstract":"<div><div>Disuse has a negative impact on the postural muscles of the trunk and legs. Different leg muscles demonstrate a differentiated and conservative response to disuse, in terms of a decrease in muscle mass, strength, aerobic performance, and changes in gene expression. We aimed to identify transcription factors regulating gene expression at baseline and after disuse in human <em>m. soleus</em> – a “slow” muscle with a strong postural function, and “mixed” <em>m. vastus lateralis</em>. Biopsies were taken from these muscles prior to and after 6 days of strict disuse (dry immersion). The enriched transcription factor binding sites (and corresponding factors) in the individual promoter regions of co-expressed genes were examined using the positional weight matrix approach. The baseline transcriptomic profiles and the disuse-induced changes (RNA-seq) differ significantly between muscles. In particular, the specific and significant response to disuse in <em>m. soleus</em> was found to be strongly related to the suppression of genes regulating the mitochondrial energy metabolism, the activation of the inflammatory response and the ubiquitin-proteasome system. This response is associated with the proinflammatory transcription factors such as families IRF, STAT, and other. The validity of approximately two-thirds of the predicted transcription factors was indirectly confirmed by the analysis of their function described in the literature. These identified transcription factors appear to be promising candidates for future targeted studies that mechanistically investigate gene expression regulation in various muscles at baseline, following disuse or inactivity.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 2","pages":"Article 195086"},"PeriodicalIF":2.6,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470039","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 regulation of gene expression and genome integrity","authors":"Sukesh R. Bhaumik","doi":"10.1016/j.bbagrm.2025.195078","DOIUrl":"10.1016/j.bbagrm.2025.195078","url":null,"abstract":"","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 1","pages":"Article 195078"},"PeriodicalIF":2.6,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076643","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}