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200 papers
Harnessing p53 for targeted cancer therapy: new advances and future directions.
Andrysik Z, Espinosa JM
Transcription · 2025 Feb · PMID 40031988 · Full text
The transcription factor p53 is the most frequently impaired tumor suppressor in human cancers. In response to various stress stimuli, p53 activates transcription of genes that mediate its tumor-suppressive functions. Di...
The transcription factor p53 is the most frequently impaired tumor suppressor in human cancers. In response to various stress stimuli, p53 activates transcription of genes that mediate its tumor-suppressive functions. Distinctive characteristics of p53 outlined here enable a well-defined program of genes involved in cell cycle arrest, apoptosis, senescence, differentiation, metabolism, autophagy, DNA repair, anti-viral response, and anti-metastatic functions, as well as facilitating autoregulation within the p53 network. This versatile, anti-cancer network governed chiefly by a single protein represents an immense opportunity for targeted cancer treatment, since about half of human tumors retain unmutated p53. During the last two decades, numerous compounds have been developed to block the interaction of p53 with the main negative regulator MDM2. However, small molecule inhibitors of MDM2 only induce a therapeutically desirable apoptotic response in a limited number of cancer types. Moreover, clinical trials of the MDM2 inhibitors as monotherapies have not met expectations and have revealed hematological toxicity as a characteristic adverse effect across this drug class. Currently, combination treatments are the leading strategy for enhancing efficacy and reducing adverse effects of MDM2 inhibitors. This review summarizes efforts to identify and test therapeutics that work synergistically with MDM2 inhibitors. Two main types of drugs have emerged among compounds used in the following combination treatments: first, modulators of the p53-regulated transcriptome (including chromatin modifiers), translatome, and proteome, and second, drugs targeting the downstream pathways such as apoptosis, cell cycle arrest, DNA repair, metabolic stress response, immune response, ferroptosis, and growth factor signaling. Here, we review the current literature in this field, while also highlighting overarching principles that could guide target selection in future combination treatments.
Harnessing transcription factors for therapeutic purposes.
Espinosa JM
Transcription · 2025 Feb · PMID 39950380 · Full text
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Beyond small molecules: advancing MYC-targeted cancer therapies through protein engineering.
Edaibis R, Akel R, Shin JA
Transcription · 2025 Feb · PMID 39878458 · Full text
Protein engineering has emerged as a powerful approach toward the development of novel therapeutics targeting the MYC/MAX/E-box network, an active driver of >70% of cancers. The MYC/MAX heterodimer regulates numerous gen...
Protein engineering has emerged as a powerful approach toward the development of novel therapeutics targeting the MYC/MAX/E-box network, an active driver of >70% of cancers. The MYC/MAX heterodimer regulates numerous genes in our cells by binding the Enhancer box (E-box) DNA site and activating the transcription of downstream genes. Traditional small molecules that inhibit MYC face significant limitations that include toxic effects, drug delivery challenges, and resistance. Recent advances in protein engineering offer promising alternatives by creating protein-based drugs that directly disrupt the MYC/MAX dimerization interface and/or MYC/MAX's binding to specific DNA targets. Designed DNA binding proteins like Omomyc, DuoMyc, ME47, MEF, and Mad inhibit MYC activity through specific dimerization, sequestration, and DNA-binding mechanisms. Compared to small molecules, these engineered proteins can offer superior specificity and efficacy and provide a potential pathway for overcoming the limitations of traditional cancer therapies. The success of these protein therapeutics highlights the importance of protein engineering in developing cancer treatments.
Hypoxia-inducible transcription factors: architects of tumorigenesis and targets for anticancer drug discovery.
McDermott A, Tavassoli A
Transcription · 2025 Feb · PMID 39470609 · Full text
Hypoxia-inducible factors (HIFs) play a pivotal role as master regulators of tumor survival and growth, controlling a wide array of cellular processes in response to hypoxic stress. Clinical data correlates upregulated H...
Hypoxia-inducible factors (HIFs) play a pivotal role as master regulators of tumor survival and growth, controlling a wide array of cellular processes in response to hypoxic stress. Clinical data correlates upregulated HIF-1 and HIF-2 levels with an aggressive tumor phenotype and poor patient outcome. Despite extensive validation as a target in cancer, pharmaceutical targeting of HIFs, particularly the interaction between α and βsubunits that forms the active transcription factor, has proved challenging. Nonetheless, many indirect inhibitors of HIFs have been identified, targeting diverse parts of this pathway. Significant strides have also been made in the development of direct inhibitors of HIF-2, exemplified by the FDA approval of Belzutifan for the treatment of metastatic clear cell renal carcinoma. While efforts to target HIF-1 using various therapeutic modalities have shown promise, no clinical candidates have yet emerged. This review aims to provide insights into the intricate and extensive role played by HIFs in cancer, and the ongoing efforts to develop therapeutic agents against this target.
From silence to symphony: transcriptional repression and recovery in response to DNA damage.
Ajit K, Gullerova M
Transcription · 2024 · PMID 39353089 · Full text
Genotoxic stress resulting from DNA damage is resolved through a signaling cascade known as the DNA Damage Response (DDR). The repair of damaged DNA is essential for cell survival, often requiring the DDR to attenuate ot...
Genotoxic stress resulting from DNA damage is resolved through a signaling cascade known as the DNA Damage Response (DDR). The repair of damaged DNA is essential for cell survival, often requiring the DDR to attenuate other cellular processes such as the cell cycle, DNA replication, and transcription of genes not involved in DDR. The complex relationship between DDR and transcription has only recently been investigated. Transcription can facilitate the DDR in response to double-strand breaks (DSBs) and stimulate nucleotide excision repair (NER). However, transcription may need to be reduced to prevent potential interference with the repair machinery. In this review, we discuss various mechanisms that regulate transcription repression in response to different types of DNA damage, categorizing them by their range and duration of effect. Finally, we explore various models of transcription recovery following DNA damage-induced repression.
Structure and function of bacterial transcription regulators of the SorC family.
Šoltysová M, Řezáčová P
Transcription · 2024 · PMID 39223991 · Full text
The SorC family is a large group of bacterial transcription regulators involved in controlling carbohydrate catabolism and quorum sensing. SorC proteins consist of a conserved C-terminal effector-binding domain and an N-...
The SorC family is a large group of bacterial transcription regulators involved in controlling carbohydrate catabolism and quorum sensing. SorC proteins consist of a conserved C-terminal effector-binding domain and an N-terminal DNA-binding domain, whose type divides the family into two subfamilies: SorC/DeoR and SorC/CggR. Proteins of the SorC/CggR subfamily are known to regulate the key node of glycolysis-triose phosphate interconversion. On the other hand, SorC/DeoR proteins are involved in a variety of peripheral carbohydrate catabolic pathways and quorum sensing functions, including virulence. Despite the abundance and importance of this family, SorC proteins seem to be on the periphery of scientific interest, which might be caused by the fragmentary information about its representatives. This review aims to compile the existing knowledge and provide material to inspire future questions about the SorC protein family.
Deciphering the dynamic code: DNA recognition by transcription factors in the ever-changing genome.
Yao YM, Miodownik I, O'Hagan MP … +2 more , Jbara M, Afek A
Transcription · 2024 · PMID 39033307 · Full text
Transcription factors (TFs) intricately navigate the vast genomic landscape to locate and bind specific DNA sequences for the regulation of gene expression programs. These interactions occur within a dynamic cellular env...
Transcription factors (TFs) intricately navigate the vast genomic landscape to locate and bind specific DNA sequences for the regulation of gene expression programs. These interactions occur within a dynamic cellular environment, where both DNA and TF proteins experience continual chemical and structural perturbations, including epigenetic modifications, DNA damage, mechanical stress, and post-translational modifications (PTMs). While many of these factors impact TF-DNA binding interactions, understanding their effects remains challenging and incomplete. This review explores the existing literature on these dynamic changes and their potential impact on TF-DNA interactions.
Negative feedback systems for modelling NF-κB transcription factor oscillatory activity.
Kochel B
Transcription · 2024 · PMID 38739365 · Full text
Low-dimensional negative feedback systems (NFSs) were developed within a signal flow model to describe the oscillatory activities of NF-κB caused by interactions with its inhibitor IκBα. The NFSs were established as 3- a...
Low-dimensional negative feedback systems (NFSs) were developed within a signal flow model to describe the oscillatory activities of NF-κB caused by interactions with its inhibitor IκBα. The NFSs were established as 3- and 4-order linear systems containing unperturbed and perturbed negative feedback (NF) loops with constant or time-varying NF strengths and a feed-forward loop. NF-related analytical solutions to the NFSs representing the time courses of NF-κB and IκBα were determined and their exact mathematical relationship was found. The NFS's parameters were determined to fit the experimental time courses of NF-κB in TNF-α-stimulated embryonic fibroblasts, embryonic fibroblasts reconstituted with RelA, C9L cells, GFP-p65 knock-in embryonic fibroblasts and embryogenic fibroblasts lacking Iκβ and IκBε, LPS-stimulated IC-21 macrophages treated or not with DCPA, and anti-IgM-stimulated DT40 B-lymphocytes. The unperturbed and perturbed NFSs describing the above biosystems generated isochronous and non-isochronous solutions, depending on a constant or time-varying NF strength, respectively. The oscillation period of the NF-coupled solutions, the phase difference between them and the time delays in the appearance of cytoplasmic IκBα after stimulation of NF-κB were determined. A significant divergence between the IκBα solutions to the NFSs and the IκBα experimental courses led to a rejection of the NF coupling between NF-κB and IκBα in the above biosystems. It was shown that neither the linearity nor the low dimensionality of the NFSs altered the NF relationship and the divergence between the IκBα solutions to the NFS and IκBα experimental time courses. Although the NF relationship between IκBα and NF-κB was not confirmed in all the experimental data analyzed, delayed negative feedback was found in some cases.
Minimization and complete loss of general transcription factor proteins in the intracellular parasite .
Belkevich AE, Khalil AY, Decatur WA … +2 more , Palumbo RJ, Knutson BA
Transcription · 2024 · PMID 38722258 · Full text
Genome compaction is a common evolutionary feature of parasites. The unicellular, obligate intracellular parasite has one of smallest known eukaryotic genomes, and is nearly four times smaller than its distant fungi rel...
Genome compaction is a common evolutionary feature of parasites. The unicellular, obligate intracellular parasite has one of smallest known eukaryotic genomes, and is nearly four times smaller than its distant fungi relative, the budding yeast . Comparison of the proteins encoded by compacted genomes to those encoded by larger genomes can reveal the most highly conserved features of the encoded proteins. In this study, we identified the proteins comprising the RNA polymerases and their corresponding general transcription factors by using several bioinformatic approaches to compare the transcription machinery of and . Surprisingly, our analyses revealed an overall reduction in the size of the proteins comprising transcription machinery of , which includes the loss of entire regions or functional domains from proteins, as well as the loss of entire proteins and complexes. Unexpectedly, we found that the ortholog of Rpc37 (a RNA Polymerase III subunit) more closely resembles the ortholog of Rpc37 than the ortholog of Rpc37, in both size and structure. Overall, our findings provide new insight into the minimal core eukaryotic transcription machinery and help define the most critical features of Pol components and general transcription factors.
Aryl hydrocarbon receptor as a drug target in advanced prostate cancer therapy - obstacles and perspectives.
Procházková J, Kahounová Z, Vondráček J … +1 more , Souček K
Transcription · 2025 Feb · PMID 38547312 · Full text
Aryl hydrocarbon receptor (AhR) is a transcription factor that is primarily known as an intracellular sensor of environmental pollution. After five decades, the list of synthetic and toxic chemicals that activate AhR sig...
Aryl hydrocarbon receptor (AhR) is a transcription factor that is primarily known as an intracellular sensor of environmental pollution. After five decades, the list of synthetic and toxic chemicals that activate AhR signaling has been extended to include a number of endogenous compounds produced by various types of cells via their metabolic activity. AhR signaling is active from the very beginning of embryonal development throughout the life cycle and participates in numerous biological processes such as control of cell proliferation and differentiation, metabolism of aromatic compounds of endogenous and exogenous origin, tissue regeneration and stratification, immune system development and polarization, control of stemness potential, and homeostasis maintenance. AhR signaling can be affected by various pharmaceuticals that may help modulate abnormal AhR signaling and drive pathological states. Given their role in immune system development and regulation, AhR antagonistic ligands are attractive candidates for immunotherapy of disease states such as advanced prostate cancer, where an aberrant immune microenvironment contributes to cancer progression and needs to be reeducated. Advanced stages of prostate cancer are therapeutically challenging and characterized by decreased overall survival (OS) due to the metastatic burden. Therefore, this review addresses the role of AhR signaling in the development and progression of prostate cancer and discusses the potential of AhR as a drug target for the treatment of advanced prostate cancer upon entering the phase of drug resistance and failure of first-line androgen deprivation therapy.: ADC: antibody-drug conjugate; ADT: androgen deprivation therapy; AhR: aryl hydrocarbon receptor; AR: androgen receptor; ARE: androgen response element; ARPI: androgen receptor pathway inhibitor; mCRPC: metastatic castration-resistant prostate cancer; DHT: 5a-dihydrotestosterone; FICZ: 6-formylindolo[3,2-b]carbazole; 3-MC: 3-methylcholanthrene; 6-MCDF: 6-methyl-1,3,8-trichlorodibenzofuran; MDSCs: myeloid-derived suppressor cells; PAHs: polycyclic aromatic hydrocarbons; PCa: prostate cancer; TAMs: tumor-associated macrophages; TF: transcription factor; TCDD, 2,3,7,8-tetrachlorodibenzo--dioxin; TME: tumor microenvironment; TRAMP: transgenic adenocarcinoma of the mouse prostate; TROP2: tumor associated calcium signal transducer 2.
Bacterial phenotypic heterogeneity through the lens of single-cell RNA sequencing.
Walls AW, Rosenthal AZ
Transcription · 2024 · PMID 38532542 · Full text
Bacterial transcription is not monolithic. Microbes exist in a wide variety of cell states that help them adapt to their environment, acquire and produce essential nutrients, and engage in both competition and cooperatio...
Bacterial transcription is not monolithic. Microbes exist in a wide variety of cell states that help them adapt to their environment, acquire and produce essential nutrients, and engage in both competition and cooperation with their neighbors. While we typically think of bacterial adaptation as a group behavior, where all cells respond in unison, there is often a mixture of phenotypic responses within a bacterial population, where distinct cell types arise. A primary phenomenon driving these distinct cell states is transcriptional heterogeneity. Given that bacterial mRNA transcripts are extremely short-lived compared to eukaryotes, their transcriptional state is closely associated with their physiology, and thus the transcriptome of a bacterial cell acts as a snapshot of the behavior of that bacterium. Therefore, the application of single-cell transcriptomics to microbial populations will provide novel insight into cellular differentiation and bacterial ecology. In this review, we provide an overview of transcriptional heterogeneity in microbial systems, discuss the findings already provided by single-cell approaches, and plot new avenues of inquiry in transcriptional regulation, cellular biology, and mechanisms of heterogeneity that are made possible when microbial communities are analyzed at single-cell resolution.
Correction.
Transcription · 2024 · PMID 38515028 · Full text
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An emerging paradigm in epigenetic marking: coordination of transcription and replication.
Fenstermaker TK, Petruk S, Mazo A
Transcription · 2024 · PMID 38378467 · Full text
DNA replication and RNA transcription both utilize DNA as a template and therefore need to coordinate their activities. The predominant theory in the field is that in order for the replication fork to proceed, transcript...
DNA replication and RNA transcription both utilize DNA as a template and therefore need to coordinate their activities. The predominant theory in the field is that in order for the replication fork to proceed, transcription machinery has to be evicted from DNA until replication is complete. If that does not occur, these machineries collide, and these collisions elicit various repair mechanisms which require displacement of one of the enzymes, often RNA polymerase, in order for replication to proceed. This model is also at the heart of the epigenetic bookmarking theory, which implies that displacement of RNA polymerase during replication requires gradual re-building of chromatin structure, which guides recruitment of transcriptional proteins and resumption of transcription. We discuss these theories but also bring to light newer data that suggest that these two processes may not be as detrimental to one another as previously thought. This includes findings suggesting that these processes can occur without fork collapse and that RNA polymerase may only be transiently displaced during DNA replication. We discuss potential mechanisms by which RNA polymerase may be retained at the replication fork and quickly rebind to DNA post-replication. These discoveries are important, not only as new evidence as to how these two processes are able to occur harmoniously but also because they have implications on how transcriptional programs are maintained through DNA replication. To this end, we also discuss the coordination of replication and transcription in light of revising the current epigenetic bookmarking theory of how the active gene status can be transmitted through S phase.
RNA polymerase collisions and their role in transcription.
Wang L
Transcription · 2024 · PMID 38357902 · Full text
RNA polymerases are the central enzymes of gene expression and function frequently in either a head-on or co-directional manner on the busy DNA track. Whether and how these collisions between RNA polymerases contribute t...
RNA polymerases are the central enzymes of gene expression and function frequently in either a head-on or co-directional manner on the busy DNA track. Whether and how these collisions between RNA polymerases contribute to transcriptional regulation is mysterious. Increasing evidence from biochemical and single-molecule studies suggests that RNA polymerase collisions function as an important regulator to fine-tune transcription, rather than creating deleterious "traffic jams". This review summarizes the recent progress on elucidating the consequences of RNA polymerase collisions during transcription and highlights the significance of cooperation and coordination between RNA polymerases.
Neural cell diversity in the light of single-cell transcriptomics.
Fernández-Moya SM, Ganesh AJ, Plass M
Transcription · 2023 · PMID 38229529 · Full text
The development of highly parallel and affordable high-throughput single-cell transcriptomics technologies has revolutionized our understanding of brain complexity. These methods have been used to build cellular maps of...
The development of highly parallel and affordable high-throughput single-cell transcriptomics technologies has revolutionized our understanding of brain complexity. These methods have been used to build cellular maps of the brain, its different regions, and catalog the diversity of cells in each of them during development, aging and even in disease. Now we know that cellular diversity is way beyond what was previously thought. Single-cell transcriptomics analyses have revealed that cell types previously considered homogeneous based on imaging techniques differ depending on several factors including sex, age and location within the brain. The expression profiles of these cells have also been exploited to understand which are the regulatory programs behind cellular diversity and decipher the transcriptional pathways driving them. In this review, we summarize how single-cell transcriptomics have changed our view on the cellular diversity in the human brain, and how it could impact the way we study neurodegenerative diseases. Moreover, we describe the new computational approaches that can be used to study cellular differentiation and gain insight into the functions of individual cell populations under different conditions and their alterations in disease.
Targeting bacterial transcription factors for infection control: opportunities and challenges.
Al-Tohamy A, Grove A
Transcription · 2025 Feb · PMID 38126125 · Full text
The rising threat of antibiotic resistance in pathogenic bacteria emphasizes the need for new therapeutic strategies. This review focuses on bacterial transcription factors (TFs), which play crucial roles in bacterial pa...
The rising threat of antibiotic resistance in pathogenic bacteria emphasizes the need for new therapeutic strategies. This review focuses on bacterial transcription factors (TFs), which play crucial roles in bacterial pathogenesis. We discuss the regulatory roles of these factors through examples, and we outline potential therapeutic strategies targeting bacterial TFs. Specifically, we discuss the use of small molecules to interfere with TF function and the development of transcription factor decoys, oligonucleotides that compete with promoters for TF binding. We also cover peptides that target the interaction between the bacterial TF and other factors, such as RNA polymerase, and the targeting of sigma factors. These strategies, while promising, come with challenges, from identifying targets to designing interventions, managing side effects, and accounting for changing bacterial resistance patterns. We also delve into how Artificial Intelligence contributes to these efforts and how it may be exploited in the future, and we touch on the roles of multidisciplinary collaboration and policy to advance this research domain. AI, artificial intelligence; CNN, convolutional neural networks; DTI: drug-target interaction; HTH, helix-turn-helix; IHF, integration host factor; LTTRs, LysR-type transcriptional regulators; MarR, multiple antibiotic resistance regulator; MRSA, methicillin resistant ; MSA: multiple sequence alignment; NAP, nucleoid-associated protein; PROTACs, proteolysis targeting chimeras; RNAP, RNA polymerase; TF, transcription factor; TFD, transcription factor decoying; TFTRs, TetR-family transcriptional regulators; wHTH, winged helix-turn-helix.
Transcription factors in the development and treatment of immune disorders.
Patalano SD, Fuxman Bass P, Fuxman Bass JI
Transcription · 2025 Feb · PMID 38100543 · Full text
Immune function is highly controlled at the transcriptional level by the binding of transcription factors (TFs) to promoter and enhancer elements. Several TF families play major roles in immune gene expression, including...
Immune function is highly controlled at the transcriptional level by the binding of transcription factors (TFs) to promoter and enhancer elements. Several TF families play major roles in immune gene expression, including NF-κB, STAT, IRF, AP-1, NRs, and NFAT, which trigger anti-pathogen responses, promote cell differentiation, and maintain immune system homeostasis. Aberrant expression, activation, or sequence of isoforms and variants of these TFs can result in autoimmune and inflammatory diseases as well as hematological and solid tumor cancers. For this reason, TFs have become attractive drug targets, even though most were previously deemed "undruggable" due to their lack of small molecule binding pockets and the presence of intrinsically disordered regions. However, several aspects of TF structure and function can be targeted for therapeutic intervention, such as ligand-binding domains, protein-protein interactions between TFs and with cofactors, TF-DNA binding, TF stability, upstream signaling pathways, and TF expression. In this review, we provide an overview of each of the important TF families, how they function in immunity, and some related diseases they are involved in. Additionally, we discuss the ways of targeting TFs with drugs along with recent research developments in these areas and their clinical applications, followed by the advantages and disadvantages of targeting TFs for the treatment of immune disorders.
RNA visualization and single-cell transcriptomics: methods and applications.
Andrysik Z, Donovan MG
Transcription · 2023 · PMID 38047544 · Full text
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Maintaining transcriptional homeostasis during cell cycle.
Ramos-Alonso L, Chymkowitch P
Transcription · 2024 · PMID 37655806 · Full text
The preservation of gene expression patterns that define cellular identity throughout the cell division cycle is essential to perpetuate cellular lineages. However, the progression of cells through different phases of th...
The preservation of gene expression patterns that define cellular identity throughout the cell division cycle is essential to perpetuate cellular lineages. However, the progression of cells through different phases of the cell cycle severely disrupts chromatin accessibility, epigenetic marks, and the recruitment of transcriptional regulators. Notably, chromatin is transiently disassembled during S-phase and undergoes drastic condensation during mitosis, which is a significant challenge to the preservation of gene expression patterns between cell generations. This article delves into the specific gene expression and chromatin regulatory mechanisms that facilitate the preservation of transcriptional identity during replication and mitosis. Furthermore, we emphasize our recent findings revealing the unconventional role of yeast centromeres and mitotic chromosomes in maintaining transcriptional fidelity beyond mitosis.
From words to complete phrases: insight into single-cell isoforms using short and long reads.
Joglekar A, Foord C, Jarroux J … +2 more , Pollard S, Tilgner HU
Transcription · 2023 · PMID 37314295 · Full text
The profiling of gene expression patterns to glean biological insights from single cells has become commonplace over the last few years. However, this approach overlooks the transcript contents that can differ between in...
The profiling of gene expression patterns to glean biological insights from single cells has become commonplace over the last few years. However, this approach overlooks the transcript contents that can differ between individual cells and cell populations. In this review, we describe early work in the field of single-cell short-read sequencing as well as full-length isoforms from single cells. We then describe recent work in single-cell long-read sequencing wherein some transcript elements have been observed to work in tandem. Based on earlier work in bulk tissue, we motivate the study of combination patterns of other RNA variables. Given that we are still blind to some aspects of isoform biology, we suggest possible future avenues such as CRISPR screens which can further illuminate the function of RNA variables in distinct cell populations.
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