{"title":"PIH1D1 and RPAP3, Components of the PAQosome: Emerging Roles in Cellular Physiology.","authors":"Mahaiwon Shadang, Riyaz Ahmad Mir","doi":"10.1080/10985549.2025.2596726","DOIUrl":"10.1080/10985549.2025.2596726","url":null,"abstract":"<p><p>The PAQosome (R2TP/PFDL complex) is a recently characterized co-chaperone of Hsp90 that orchestrates the assembly and stabilization of diverse macromolecular protein complexes essential for cellular homeostasis. It consists of RUVBL1, RUVBL2, PIH1D1, RPAP3 and a PFDL module consisting of prefoldin and prefoldin-like proteins. RPAP3 and PIH1D1 are subunits exclusively for the R2TP complex, and they act as central adaptors through their interactions with RUVBL1/2, Hsp90 and clients. Originally described in the context of ribonucleoprotein and PIKK assembly, evolving evidence now implicates PIH1D1 and RPAP3 in a broad spectrum of biological processes, including ciliogenesis, RNA silencing, DNA damage response, metabolic regulation, and oncogenesis. The mechanistic basis of substrate recognition, the phosphorylation-independent interactions, and the functional contribution of alternative PAQosome assemblies remain limited. This review highlights PIH1D1 and RPAP3 as dynamic proteins at the crossroads of protein homeostasis, signaling pathways, and diseases.</p>","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"375-390"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145804904","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}
{"title":"Xiangpi Shengji Ointment Accelerates Anal Fistula Healing by Regulating Macrophage-Fibroblast Crosstalk Through the Nuclear Factor Kappa B/Hypoxia-Inducible Factor Alpha/Vascular Endothelial Growth Factor Signaling Axis.","authors":"Kui Li, Jiaqing Xiong, Sai Yang, Mintao Jian","doi":"10.1080/10985549.2025.2597464","DOIUrl":"10.1080/10985549.2025.2597464","url":null,"abstract":"<p><p>This study elucidates the molecular mechanism by which Xiangpi Shengji ointment (Xiangpi Shengji gao, XPSJG) promotes anal fistula wound healing. Integrated network pharmacology and transcriptomic analyses (GSE28914, GSE203244) revealed the involvement of the NF-κB/HIF-α/VEGF axis, with elevated expression of NF-κB, HIF1A, and VEGFA observed during the early healing phase (days 3 and 7). Single-cell RNA sequencing further indicated that activation of this signaling axis may drive early macrophage M1 polarization. In vitro experiments confirmed early treatment with the aqueous extract of XPSJG powder significantly enhanced macrophage M1 polarization and upregulated VEGF, COL1A1, and α-SMA, promoting fibroblast proliferation and migration (assessed via CCK-8, ELISA, WB, RT-qPCR). In vivo, using a murine anal fistula model, XPSJG accelerated wound closure, improved tissue architecture, and reduced inflammation and apoptosis through modulation of the NF-κB/HIF-α/VEGF axis. These effects were partially reversed by an NF-κB inhibitor, further verifying pathway involvement. Collectively, the findings demonstrate that early application of XPSJG facilitates anal fistula healing by inducing macrophage M1 polarization and enhancing fibroblast function via the NF-κB/HIF-α/VEGF signaling axis, thereby providing a mechanistic rationale for its clinical use in chronic wound management.</p>","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"336-360"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850367","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}
Avani A Deshpande, John H Lockhart, Marco Napoli, Elsa R Flores
{"title":"Lnc-ing the Hallmarks of Cancer: The Interplay between lncRNAs and the p53 Family Members across the Hallmarks of Cancer.","authors":"Avani A Deshpande, John H Lockhart, Marco Napoli, Elsa R Flores","doi":"10.1080/10985549.2026.2662223","DOIUrl":"10.1080/10985549.2026.2662223","url":null,"abstract":"<p><p>The fascinating world of long non-coding RNAs (lncRNAs) has expanded significantly over the past two decades, and their characterization has revealed their involvement in a variety of biological processes both in physiological and pathological contexts. Here, we review the crosstalk between lncRNAs and the p53 family of transcription factors in cancer, with particular emphasis on the molecular features that enable cells to become malignant, progress, and metastasize. Finally, we discuss how this knowledge is currently being translated into the clinic, including the use of lncRNAs as biomarkers and therapeutic targets.</p>","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"766-785"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147874799","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}
{"title":"<i>dif</i>-XerCD is Required for Chromosome Segregation During cSDR-Dependent Growth in <i>Escherichia coli</i>.","authors":"Taku Tanaka, Rino Fukatsu, Yumika Seki, Hiroyuki Sasanuma, Hisao Masai","doi":"10.1080/10985549.2026.2712295","DOIUrl":"10.1080/10985549.2026.2712295","url":null,"abstract":"<p><p><i>Escherichia coli</i> cells can grow in a DnaA- and <i>oriC</i>-independent manner in <i>rnhA</i>-deficient cells that lack the major RNaseH activity. This mode of replication is named cSDR (constitutive stable DNA replication) and is believed to initiate from the sites of RNA-DNA hybrids, although the detailed mechanisms of cSDR are unclear. In this study, we discovered that <i>dif</i> sequence and XerC/D are essential for cSDR-dependent growth. cSDR was observed in either <i>dif</i> or <i>xerC/D</i> mutant cells as efficiently as in the control cells, as measured by the incorporation of [<sup>3</sup>H]-thymine. However, we found that these mutants accumulate cells with extra DNA contents in the presence of rifampicin and cefalexin, suggesting accumulation of unresolved dimeric or multimeric chromosomes or that of catenated chromosomes due to potential problems in resolution of the replicated chromosomes or in decatenation process. These results indicate that site-specific recombination mediated by <i>dif</i>-XerC/D is essential for cSDR-dependent growth.</p>","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"1017-1034"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795513","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}
Bridget M Walker, Jonathan Y Chung, Haleigh G Pascual, Jyoti D Adala, Bruce A Knutson
{"title":"Molecular Mechanisms of RNA Polymerase I Transcription in Health and Disease: An Overview.","authors":"Bridget M Walker, Jonathan Y Chung, Haleigh G Pascual, Jyoti D Adala, Bruce A Knutson","doi":"10.1080/10985549.2026.2628826","DOIUrl":"10.1080/10985549.2026.2628826","url":null,"abstract":"<p><p>RNA polymerase I (Pol I) is a specialized eukaryotic enzyme responsible for transcribing ribosomal DNA into precursor rRNA, a process that initiates ribosome biogenesis and supports cellular growth, metabolism, and proliferation. Recent structural and mechanistic studies have revealed unique features of Pol I architecture that enable high transcriptional output and tight regulatory control. Pol I activity is dynamically regulated by signaling pathways, epigenetic mechanisms, and chromatin structure, integrating environmental and metabolic cues to fine-tune ribosome production. Dysregulation of Pol I transcription is associated with a wide spectrum of human diseases: hyperactivation is a hallmark of cancer, whereas loss-of-function mutations cause ribosomopathies, leukodystrophies, and neurodegenerative disorders through nucleolar stress. Targeted therapies, including small-molecule inhibitors and emerging peptide-based approaches, are expanding clinical strategies to modulate Pol I activity. Beyond its canonical role, Pol I contributes to genome stability, immune regulation, and host-pathogen interactions, broadening its therapeutic relevance. This review integrates structural, mechanistic, and disease perspectives on Pol I, highlighting how fundamental discoveries are informing the next generation of targeted interventions across oncology, neurodegeneration, developmental disorders, infection, and aging.</p>","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"524-545"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147271390","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}
{"title":"From Genome Guardian to Immune Modulator: The Expanding Roles of Tumor Suppressor p53.","authors":"Weiwei Wang, Juan Liu, Zhaohui Feng, Wenwei Hu","doi":"10.1080/10985549.2025.2571187","DOIUrl":"10.1080/10985549.2025.2571187","url":null,"abstract":"<p><p>p53 is a key tumor suppressor, and mutations in the p53 gene occur in more than half of all human cancers. p53, which is under tight and complex regulation in cells, functions primarily as a transcription factor regulating genes involved in many cellular processes, including cell cycle arrest, apoptosis, senescence, ferroptosis, and metabolism, thereby maintaining genomic integrity and preventing tumorigenesis. While the cell-intrinsic functions of p53, which contribute to its tumor-suppressive activity, have been extensively studied, it is now clear that p53 also plays an important role in immune regulation, a connection first observed when p53 was identified as a cellular protein interacting with viral antigens. Growing evidence shows that p53 modulates both innate and adaptive immunity by regulating cytokine production, antigen presentation, and the functions of immune cells, thereby contributing to host defense against infections, inflammatory responses, and antitumor immunity. In this review, we summarize and discuss the multifaceted roles of p53 and its signaling in regulating immune functions and their implications in human diseases, particularly cancer. A better understanding of the immune-related functions of p53 is crucial for advancing cancer treatment and broadening insights into immunity and disease.</p>","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"78-95"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145346259","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}
Qiuhua Xie, Ling Ma, Wanzhi Cai, Hu Li, Yuange Duan
{"title":"How Particular RNA Editing Sites Can be Selectively Superior to Heterozygous SNPs Independent of Temporospatial Regulation.","authors":"Qiuhua Xie, Ling Ma, Wanzhi Cai, Hu Li, Yuange Duan","doi":"10.1080/10985549.2025.2603947","DOIUrl":"10.1080/10985549.2025.2603947","url":null,"abstract":"<p><p>A-to-I RNA editing introduces A-to-G variation at post-transcriptional level, but it remains mysterious. What is the advantage of functional RNA editing compared to an A/G heterozygous SNP? Here, we provide the following situations that particular RNA editing sites can be superior to heterozygous SNPs even independent of its temporospatial regulation. (1) Assume a site with A/G heterozygote advantage. RNA editing does not undergo Mendelian segregation and recombination that inevitably produce homozygotes of lower fitness. (2) Graded RNA editing level. A snapshot of editing profile shows strong tissue-specific editing levels, providing flexible stoichiometry of edited/unedited versions, while heterozygous SNPs generally produce similar expression of two alleles. (3) Higher molecular diversity. N RNA editing sites in a gene theoretically produce a dramatic number of X = 2<sup>N</sup> mRNA haplotypes, but all SNPs in a gene can only produce two alleles. Nevertheless, we emphasize that these advantageous sites may emerge through complicated evolutionary process and remain rare across the genome. We systematically discussed the pros and cons of RNA editing versus heterozygous SNPs, deepening our understanding of the biological functions of <i>cis</i>-regulatory mechanisms. We provide putative answers to why evolution chose RNA editing instead of a genomic mutation at particular sites.</p>","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"238-252"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900838","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}
{"title":"The Novel Compound SIC-19 Triggers CUL4B-Mediated Ubiquitination and Degradation of SIK2.","authors":"Yeqiu Zou, Jiaqi Liu, Shunpeng Zhu, Qian Li, Quan Li, Fang Wang, Youguo Chen, Jinhua Zhou","doi":"10.1080/10985549.2026.2669532","DOIUrl":"10.1080/10985549.2026.2669532","url":null,"abstract":"<p><p>Small-molecule inhibitors represent a novel potential therapeutic for tumors. Our previous work identified SIC-19, a small molecule compound that induces degradation of salt-inducible kinase 2 (SIK2), leading to apoptosis and reduced proliferation in tumor, expecting to be a promising clinical treatment for ovarian cancer. While we initially observed that SIC-19 triggers SIK2 ubiquitination, the underlying mechanism was unknown. Here we elucidate this process by demonstrating that SIC-19 promotes the interaction between SIK2 and the CUL4B-DDB1 E3 ubiquitin ligase. Mass spectrometry discovered several ubiquitin ligases that bind to SIK2. Immunoprecipitation assays revealed that the CUL4B-DDB1 ligase is an interaction partner of SIK2. Through Western blot analysis, we demonstrated that CUL4B is functionally required for SIC-19-induced ubiquitination and SIK2 degradation. The ubiquitination and half-life of SIK2 are directly correlated with the dosage of SIC-19 and the expression of CUL4B. Site-directed mutagenesis and ubiquitination assays further confirmed that lysine 144 (K144) is the critical residue in SIK2 that regulates cancer behavior as cell proliferation and migration by leading to the degradation of SIK2. Our findings define a novel mechanism wherein SIC-19 induces CUL4B-dependent ubiquitination and degradation of SIK2, possesses the potential to act as an inhibitor, and may subsequently be developed as a targeted agent.</p>","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"809-825"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148055715","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}
Karen McMurdie, Allison N Peeney, Melissa A Mefford, Peter Baumann, David C Zappulla
{"title":"<i>Schizosaccharomyces pombe</i> Telomerase RNA: Secondary Structure and Flexible-Scaffold Function.","authors":"Karen McMurdie, Allison N Peeney, Melissa A Mefford, Peter Baumann, David C Zappulla","doi":"10.1080/10985549.2025.2571189","DOIUrl":"10.1080/10985549.2025.2571189","url":null,"abstract":"<p><p>The telomerase RNA-protein enzyme is critical for most eukaryotes to complete genome copying by extending chromosome ends, thus solving the end-replication problem and postponing senescence. Despite the importance of the fission yeast <i>Schizosaccharomyces pombe</i> to biomedical research, very little is known about the structure of its 1212 nt telomerase RNA. We have determined the secondary structure of this large RNA, TER1, based on phylogenetics and bioinformatic modeling, as well as genetic and biochemical analyses. We find several conserved regions of the rapidly evolving TER1 RNA are important to maintain telomeres, based on testing truncation mutants <i>in vivo</i>, whereas many other large regions are dispensable. This is similar to budding yeast telomerase RNA, and consistent with functioning as a flexible scaffold for the RNP. We tested if the essential three-way junction works from other locations in TER1, finding that it can, supporting that it is flexibly scaffolded. Furthermore, we find that a half-sized Mini-TER1 allele, built from the catalytic core and the three-way junction, reconstitutes catalytic activity with TERT <i>in vitro</i>. Overall, we provide a secondary structure model for the large fission-yeast telomerase lncRNA, based on phylogenetics and molecular-genetic testing in cells, and insight into the RNP's physical and functional organization.</p>","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"96-113"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13058752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145635802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amala Kaja, Bhawana Uprety, Pritam Chakraborty, Sukesh R Bhaumik
{"title":"Distinct Functions of the Tor1 and Tor2 Kinases in Regulation of the Ribosomal Protein Gene Expression via TORC1, Not TORC2.","authors":"Amala Kaja, Bhawana Uprety, Pritam Chakraborty, Sukesh R Bhaumik","doi":"10.1080/10985549.2025.2587084","DOIUrl":"10.1080/10985549.2025.2587084","url":null,"abstract":"<p><p>The serine/threonine kinase, TOR (target of rapamycin), exists in two complexes, namely TORC1 (with either Tor1 or Tor2 kinase) and TORC2 (that contains Tor2, but not Tor1), and its pharmacological inhibition by rapamycin impairs the PIC (pre-initiation complex) formation at the ribosomal protein genes (and hence transcription and ribosome biogenesis). However, TOR's involvement in such gene regulation has not been elucidated genetically at the level of Tor1, Tor2, TORC1 or TORC2. Here, we demonstrate that null mutation of <i>TOR1</i> and short-term depletion of its expression do not affect the PIC formation (and transcription) at the ribosomal protein genes. Likewise, PIC formation and transcription are not altered in TORC2-specific <i>tor2</i>-tsA conditional mutant or following short-term depletion of <i>TOR2</i> expression. These results support the dispensability of TORC2 for ribosomal protein gene expression, and indicate that Tor1 and Tor2 play redundant roles via TORC1 for PIC formation, and hence transcription. In agreement, the <i>Δtor1</i> mutant in combination with both TORC1 and TORC2-specific <i>tor2-</i>tsC conditional mutation impairs PIC formation at the ribosomal protein genes with consequent reduction in transcription. Collectively, our genetic analysis support redundant, yet distinct, functions of Tor1 and Tor2 via TORC1, not TORC2, in regulation of the ribosomal protein gene expression.</p>","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"168-186"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145677699","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}