Molecular And Cellular Biology[JOURNAL]
Sun
200 papers
Recent Insights into Mechanisms Regulating the Proteasome: Implications for Human Disease.
Sumikama R, Shibata Y, Wu R … +1 more , Murata S
Mol Cell Biol · 2026 · PMID 41263410 · Publisher ↗
Since its discovery several decades ago, the proteasome has been recognized as one of the most complex and highly evolved proteolytic systems. Through the selective and rapid degradation of ubiquitinated proteins, it pla...
Since its discovery several decades ago, the proteasome has been recognized as one of the most complex and highly evolved proteolytic systems. Through the selective and rapid degradation of ubiquitinated proteins, it plays a pivotal role in maintaining cellular proteostasis and governing essential biological processes such as cell cycle regulation and signal transduction. Recent advances in cryo-electron microscopy (cryo-EM), together with developments in mass spectrometry and large-scale genetic screening, have provided unprecedented insights into proteasome biology. These approaches have not only revealed the proteasome as a precisely engineered molecular machine optimized for substrate specificity and efficient degradation, but have also facilitated the identification of previously unrecognized regulatory factors and post-translational modifications that fine-tune its activity. Moreover, accumulating evidence has demonstrated that proteasome capacity is tightly regulated at multiple levels, including transcriptional control, assembly dynamics, and subcellular localization, to meet diverse cellular demands and preserve proteostasis. Importantly, dysregulation of these processes is linked to human diseases, underscoring the proteasome's central role in cellular physiology and its promise as a therapeutic target. Ongoing research is uncovering new regulatory layers and structural complexities, highlighting the proteasome's indispensable and versatile role in health and disease.
Cholesterol Transport from ER to Outer Mitochondria by ERLIN2 in Steroid Metabolism.
Bose HS, Burak WE, Whittal RM
Mol Cell Biol · 2026 · PMID 41251286 · Publisher ↗
Cholesterol trafficking from the endoplasmic reticulum (ER) through the mitochondria-associated ER membrane (MAM) and finally to mitochondria is essential for mammalian survival. ER lipid raft-associated protein 2 (ERLIN...
Cholesterol trafficking from the endoplasmic reticulum (ER) through the mitochondria-associated ER membrane (MAM) and finally to mitochondria is essential for mammalian survival. ER lipid raft-associated protein 2 (ERLIN2) scaffolds raft-like microdomains in the trans-Golgi network, endosomes, and plasma membrane. We found that ERLIN2 assists in rolling cholesterol trafficking-associated lipid vesicles by facilitating the intermediate folding of cholesterol trafficker steroidogenic acute regulatory protein (StAR) from the ER to MAM prior to delivery to the outer mitochondrial membrane. Each ERLIN2-StAR interaction is short. The absence of ERLIN2 ablates mitochondrial cholesterol transport. Over time, StAR association with ERLIN2 increases from the ER to MAM, thereby enhancing mitochondrial cholesterol transport. Thus, ERLIN2 is central for regulating mitochondrial cholesterol trafficking required for mitochondrial steroid metabolism.
Correction.
Mol Cell Biol · 2025 Nov · PMID 41236368 · Publisher ↗
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Low-Dose Caffeine Exposure Protects the Human Genome from Ionizing Radiation-Induced Damage and Prolongs Mouse Longevity.
Kumari S, Vartak SV, Tamang S … +4 more , Desai SS, Mukerjee S, Choudary B, Raghavan SC
Mol Cell Biol · 2026 · PMID 41231152 · Publisher ↗
Coffee is one of the most widely consumed beverages in the world and is a rich source of caffeine, a methylxanthine. Here we show that exposure to caffeine significantly reduces ionizing radiation (IR) induced DNA breaks...
Coffee is one of the most widely consumed beverages in the world and is a rich source of caffeine, a methylxanthine. Here we show that exposure to caffeine significantly reduces ionizing radiation (IR) induced DNA breaks and resulted in no or minimal G2/M arrest within the human cell, in contrast to IR alone. At the molecular level, we demonstrate that when naked plasmid DNA or oligomeric DNA was irradiated, the number of breaks was significantly less in the presence of caffeine. The observed radioprotection was irrespective of its sequence and was due to quenching of ROS by caffeine. Besides, caffeine treatment in NOS2 knockout (KO) mice exhibited a significantly enhanced survival compared to the corresponding WT mice post-irradiation. The transcriptome analysis revealed the upregulation of the key antioxidant genes (Gpx3, Gpx7, Gpx4, Idh1, etc.) involved in playing a role in ROS homeostasis in caffeine-treated mice following exposure to IR, which was further upregulated in the NOS2 KO mice. The increase in lifespan after whole-body irradiation in mice pretreated with caffeine demonstrates the potential of caffeine-mediated radioprotection and provides compelling evidence that caffeine mitigates the detrimental effects of ionizing radiation by reducing ROS and RNS levels and enhancing the expression of antioxidant genes.
Pharmacological Modulation of Autophagy Corrects Cellular Defects in Pediatric Crohn's Disease.
Creoli M, Buono P, Cenni S … +12 more , Casertano M, Vitale A, Maglio M, Polishchuk R, Polishchuk E, Cinque L, Miele E, Martinelli M, Settembre C, Staiano A, Dolce P, Strisciuglio C
Mol Cell Biol · 2026 · PMID 41231025 · Publisher ↗
Crohn's disease (CD) is an inflammatory gastrointestinal disorder marked by impaired autophagy due to inefficient bacterial uptake. We studied the effects of autophagy modulation using Tat-beclin-1 and carbamazepine (CBZ...
Crohn's disease (CD) is an inflammatory gastrointestinal disorder marked by impaired autophagy due to inefficient bacterial uptake. We studied the effects of autophagy modulation using Tat-beclin-1 and carbamazepine (CBZ) on dendritic cells (DCs) and Paneth cell functionality in pediatric CD patients. Twenty CD children genotyped for the ATG16L1 rs2241880 polymorphism and 10 healthy controls were enrolled. DCs were incubated with fluorochrome-conjugated particles of or DQ-ovalbumin after pretreatment with CBZ or Tat-beclin-1 to evaluate antigen processing. Treated DCs were stained for P62, LAMP1, and LC3, and analyzed by confocal microscopy. Paneth cells from biopsies were pretreated with both drugs, stained for lysozyme, and analyzed by transmission electron microscopy. Antigen processing increased after Tat-beclin-1 and CBZ treatment in all groups. DCs expressed higher activation markers HLA-DR and CD86+, notably in high-risk patients, who also showed increased DQ-OVA processing. The number of lysozymes in Paneth cells from controls did not change after Tat-beclin-1 treatment, while in the CD group, it decreased significantly, suggesting increased exocytosis. CBZ treatment increased secretory granules only in CD inflamed tissue. Our results indicate that CBZ and Tat-beclin-1 enhance autophagic flux, representing a novel approach to treating pediatric CD patients.
From Genome Guardian to Immune Modulator: The Expanding Roles of Tumor Suppressor p53.
Wang W, Liu J, Feng Z … +1 more , Hu W
Mol Cell Biol · 2026 Jan · PMID 41128159 · Publisher ↗
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 regulati...
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.
From Biogenesis to Breakdown: How Protein Biogenesis and Quality Control Failures Drive Mitochondrial Disease.
Leeming PJ, Mercuri-Svik J, Stojanovski D
Mol Cell Biol · 2026 Jan · PMID 41105521 · Publisher ↗
Mitochondria rely on the coordinated function of over 1000 proteins, most of which are nuclear-encoded, synthesized in the cytosol, and imported into distinct mitochondrial sub-compartments. Thirteen additional proteins...
Mitochondria rely on the coordinated function of over 1000 proteins, most of which are nuclear-encoded, synthesized in the cytosol, and imported into distinct mitochondrial sub-compartments. Thirteen additional proteins are synthesized within the organelle itself, forming core components of the oxidative phosphorylation (OXPHOS) system. Once inside, mitochondrial precursors undergo precise maturation, folding, and assembly, supported by specialized factors that ensure their function. These processes are safeguarded by an intricate network of chaperones, proteases, and disaggregases that maintain proteome integrity. Protein biogenesis and quality control are deeply interconnected, operating continuously to preserve mitochondrial function. Disruption at any stage, whether in import, folding, assembly, or degradation, can lead to proteotoxic stress and mitochondrial dysfunction, underlying a wide spectrum of mitochondrial diseases. Despite progress in characterizing many of these pathways in human cells, large gaps in knowledge remain. A complete understanding of protein biogenesis and surveillance mechanisms is essential to uncover how their dysregulation drives disease. This knowledge will be foundational for interpreting pathogenic mutations, predicting disease mechanisms, and ultimately guiding therapeutic strategies aimed at restoring mitochondrial proteostasis and health.
Metabolic Regulation of Copper Homeostasis Governs the Sec61-Dependent Protein Translocation Process in .
Anjana V, Anand S, Thakur P … +8 more , Pal R, Acharjee S, Sharma S, Awachat SS, Manjhi R, Rejidev D, Singh R, Tomar RS
Mol Cell Biol · 2026 Jan · PMID 41085287 · Publisher ↗
The concentration of cellular labile pool of copper must be strictly regulated because disruption in copper homeostasis results in diseases. In , elevated levels of labile copper impair cell viability by inhibiting Sec61...
The concentration of cellular labile pool of copper must be strictly regulated because disruption in copper homeostasis results in diseases. In , elevated levels of labile copper impair cell viability by inhibiting Sec61-mediated protein translocation into the endoplasmic reticulum. We investigated how metabolic pathways, specifically mitochondrial respiration and autophagy, contribute to copper homeostasis and the translocation of secretory proteins. We show that copper selectively inhibits protein translocation in yeast cells grown in minimal medium but not in a rich medium, highlighting a critical role of nutrients in modulating copper toxicity. Supplementation of specific amino acids suppresses the copper-induced defects in protein translocation and cell death, identifying amino acids as suppressors of the copper toxicity. Using a panel of gene deletion mutants affecting mitochondrial functions, autophagy, peroxisomes, and lipid droplets, we demonstrate that metabolic pathways regulate subcellular concentration of copper and translocation of secretory proteins. Further, disruption of redox and pH homeostasis, and pharmacological inhibition of respiration, reveals that correct subcellular concentration of copper is essential to prevent inhibitory effects on protein translocation. Together, our findings provide mechanistic insights into how metabolic status influences cellular copper homeostasis and the secretory pathway of proteins, with broader implications for understanding diseases of copper metabolism.
The Role of Tumor-Intrinsic HuR in Modeling the Pancreatic Tumor Microenvironment: Molecular Mechanisms and Therapeutic Opportunities.
Pelz KR, Gribbin KP, Sevetson T … +1 more , Brody JR
Mol Cell Biol · 2025 · PMID 41081532 · Full text
Pancreatic ductal adenocarcinoma (PDAC) remains largely refractory to therapy, due in part to the complex interplay between tumor cells and their microenvironment. Human antigen R (HuR/ELAVL1), a ubiquitously expressed R...
Pancreatic ductal adenocarcinoma (PDAC) remains largely refractory to therapy, due in part to the complex interplay between tumor cells and their microenvironment. Human antigen R (HuR/ELAVL1), a ubiquitously expressed RNA-binding protein, is emerging as an important regulator both of tumor-intrinsic and tumor-extrinsic pathways that govern PDAC progression. While the role of HuR in promoting cancer cell survival under stress is well established, recent studies reveal its broader role in shaping the tumor microenvironment (TME), including metabolic rewiring, stromal activation, angiogenesis, and immune modulation. In this review, we examine how tumor-intrinsic HuR drives epithelial-mesenchymal transition, stabilizes key transcripts involved in metabolic adaptation, and alters the tumor secretome to influence extracellular matrix deposition and fibroblast behavior. We further explore the role of HuR in regulating immune cell function and the immune landscape of PDAC. Notably, HuR-driven TME remodeling reinforces environmental stressors that further activate HuR, establishing a feed-forward loop that drives disease progression. These findings underscore HuR as a central regulator of the PDAC TME and therapeutic resistance, and thus, highlight its potential as a target in PDAC.
Deciphering the m6A Epitranscriptomic Landscape of mRNAs in Breast Cancer Cells.
Athanasopoulou K, Adamopoulos PG, Tsiakanikas P … +5 more , Daneva GN, Prassas I, Yousef GM, Diamandis EP, Scorilas A
Mol Cell Biol · 2025 · PMID 41047957 · Publisher ↗
N6-methyladenosine (m6A), the most prevalent modification in mRNAs, influences mRNA stability, splicing, and translation. Dysregulation of m6A patterns has been linked to various diseases, including cancer, highlighting...
N6-methyladenosine (m6A), the most prevalent modification in mRNAs, influences mRNA stability, splicing, and translation. Dysregulation of m6A patterns has been linked to various diseases, including cancer, highlighting its significance in cellular homeostasis. However, accurate detection and precise quantification of m6A sites within individual transcripts remains challenging. In this study, we employed nanopore sequencing to achieve transcriptome-wide, base-resolution map of the m6A methylome in human breast cancer cells. By investigating m6A distribution across breast cancer cell lines and implementing a CRISPR/Cas9-based knockout of the major m6A eraser ALKBH5, we provide insights into the differential methylation levels and motif-specific characteristics of m6A transcriptomic sites. We elucidated the m6A epitranscriptome in five well-established breast cancer cell lines derived from distinct molecular subtypes of the disease and confirmed a DRACH-dependent activity of ALKBH5. Comparative methylation analysis with the non-cancerous MCF-10A cell line revealed that MCF-7 and BT-474 breast cancer cells are primarily hypomethylated, while BT-20, MDA-MB-231 and SK-BR-3 cells show widespread hypermethylation. These cell line-based patterns highlight the potential regulatory role of m6A in breast cancer heterogeneity. Overall, our findings enhance the understanding of m6A dynamics in breast cancer.
Effects of DNA Methylation Inhibitors on Molecular and Structural Changes in Chromatin Organization in Leukemia Cells.
Sareło P, Kaczorowska A, Gąsior-Głogowska M … +9 more , Godkowicz K, Lamperska W, Drobczyński S, Zioło E, Licznerska A, Wróbel T, Podbielska H, Kałas W, Kopaczyńska M
Mol Cell Biol · 2026 Jan · PMID 41020559 · Publisher ↗
DNA methylation inhibitors are widely used in treating myeloid malignancies, yet their precise effects on chromatin organization and nuclear architecture remain incompletely understood. Here, the integrated molecular, ce...
DNA methylation inhibitors are widely used in treating myeloid malignancies, yet their precise effects on chromatin organization and nuclear architecture remain incompletely understood. Here, the integrated molecular, cellular, and biophysical approaches to investigate the impact of azacitidine (AZA) and decitabine (DEC) on chromatin structure and nuclear mechanics in AML-007 leukemia cells are presented. Confocal microscopy revealed drug-induced alterations in nuclear morphology and actin cytoskeleton organization, with DEC inducing significant nuclear enlargement and disorganization at lower concentrations (1.0 µM) compared to AZA (5.0 µM). Chromatin condensation assays demonstrated that DEC increased chromatin accessibility in a concentration-dependent manner, while AZA produced subtler effects. Optical tweezers measurements showed both agents reduced nuclear stiffness, with DEC exerting a greater impact. Spectroscopic analysis confirmed differential drug incorporation into DNA, with higher methylation loss and structural changes observed following DEC treatment. Refractive index mapping revealed chromatin decompaction, aligning with increased accessibility and nuclear softening. These findings demonstrate that DNA hypomethylating agents exert distinct, concentration-dependent effects on nuclear organization and chromatin structure, which can be quantified through molecular and biophysical readouts. This study underscores the value of integrative methods for revealing epigenetic drug effects on chromatin architecture in leukemia cells.
Loss of E-Cadherin Alters Cigarette Smoke Extract (CSE)-Induced Damage and Repair Responses in Human Airway Epithelial Cells; Implications for Chronic Obstructive Pulmonary Disease (COPD).
Zheng X, Nwozor KO, Jonker M … +3 more , Wisman M, Nawijn MC, Heijink IH
Mol Cell Biol · 2025 · PMID 41020432 · Publisher ↗
COPD is characterized by airway epithelial barrier dysfunction. We hypothesized that downregulation of E-cadherin results in abnormal responses to cigarette smoke extract (CSE) with impaired repair and increased pro-infl...
COPD is characterized by airway epithelial barrier dysfunction. We hypothesized that downregulation of E-cadherin results in abnormal responses to cigarette smoke extract (CSE) with impaired repair and increased pro-inflammatory activity. We used CRISPR-Cas9-engineered 16HBE cells with 1-2 copies of the gene encoding E-cadherin ( or ) to study effects on tight junctional protein zonula occludens (ZO-1), CSE-induced epithelial barrier dysfunction using electric cell-substrate impedance sensing and pro-inflammatory cytokine production. In airway epithelial cells (AECs) from nine COPD stage IV transplant lungs and tracheobronchial tissue of nine non-COPD donors, we assessed E-cadherin, ZO-1 and pro-inflammatory cytokines. Lower electrical resistance in 16HBE cells was accompanied by ZO-1 delocalization. CSE exposure induced transient barrier dysfunction, from which cells recovered more slowly than cells. Similarly, cells showed a delayed repair response upon wounding, while gene expression and secretion of pro-inflammatory cytokines were higher in unexposed cells (CXCL8, IL-1α) and/or showed a stronger CSE-induced increase (IL-1α, GM-CSF). AECs from COPD patients displayed lower E-cadherin and TJP1 levels and higher CSE-induced expression compared to control. Downregulation of E-cadherin resulted in disrupted ZO-1 expression, aggravated CSE-induced barrier dysfunction, impaired recovery from injury and a more pro-inflammatory epithelial phenotype in 16HBE cells.
Site Specific and Orientation Dependent CTCF Binding Determines VDJ Recombination at Murine Locus.
Yadav M, Sharma S, Rajalekshmi SR … +4 more , Bhasin N, Yimdjo J, Pfeifer K, Srivastava M
Mol Cell Biol · 2025 · PMID 40965216 · Publisher ↗
CTCF is a multifunctional protein that mediates long-range -DNA interactions in mammalian genomes. Chromatin architecture governs spatial and functional interactions of gene regulatory elements at various loci and is imp...
CTCF is a multifunctional protein that mediates long-range -DNA interactions in mammalian genomes. Chromatin architecture governs spatial and functional interactions of gene regulatory elements at various loci and is impacted by the ability of CTCF to restrict cohesin complex dependent chromatin extrusion. In addition, at antigen receptor loci, long-range interactions facilitate spatial proximity of gene segments for VDJ recombination that generates functional genes encoding immunoglobulins and T-cell receptors in developing lymphocytes. To investigate the role of CTCF in VDJ recombination, we mutated CTCF binding sites (CBS) of murine locus. Our analysis revealed that CBS interspersed in the domain encompassing variable gene segments (Vb) are not redundant. They exhibit independent but additive effects on dynamic chromatin organization leading to distinct VDJ recombination profiles in CBS mutants depending on positions of mutated CBS relative to Vb segments. Further, inversion of a single CBS drastically altered the chromatin loop organization and VDJ recombination profile. Our results demonstrate the critical importance of chromatin extrusion for generation of chromatin loops for VDJ recombination and underscore its dynamic impediment by CTCF binding at specific points within Vb segment domain to be essential to diversify the usage of Vb segments for VDJ recombination at locus.
Lactate as an Exercise Mimetic: Mitigating Disuse Atrophy and Improving Muscle Endurance in Aging SAMP8 Mice.
Qi Z, Liu X, Chen Y … +4 more , Zhang L, Yang L, Huang C, Lin D
Mol Cell Biol · 2025 · PMID 40958628 · Publisher ↗
Lactate, historically considered a metabolic byproduct, has emerged as a key regulator of muscle physiology and metabolism. This study explores its potential as an exercise mimetic to counteract disuse muscle atrophy (DM...
Lactate, historically considered a metabolic byproduct, has emerged as a key regulator of muscle physiology and metabolism. This study explores its potential as an exercise mimetic to counteract disuse muscle atrophy (DMA) in aging skeletal muscle using a hindlimb suspension model in senescence-accelerated prone 8 (SAMP8) mice. The mice were divided into four groups: Control, lactate-treated control, hindlimb suspension, and hindlimb suspension with lactate intervention. Lactate administration preserved gastrocnemius muscle mass, restored muscle strength, and attenuated oxidative fiber atrophy. Electrophoretic and histological analyses showed increased MyHC I expression, indicating protection of oxidative fibers. Functional assessments revealed improved muscle endurance and contractile force, while metabolomic profiling identified changes in energy metabolism, amino acid metabolism, and protein synthesis pathways. Specifically, lactate improved impaired branched-chain amino acid metabolism, suggesting enhanced protein synthesis. In addition, lactate boosted Cori cycle activity, upregulated hepatic lactate transporters, and increased lactate dehydrogenase B activity, facilitating efficient lactate metabolism and gluconeogenesis. These results provide new insights into the role of lactate as a metabolic regulator and highlight its potential as a therapeutic intervention to combat exercise-induced muscle wasting and preserve muscle function in aging and immobilized individuals.
Histone Acetyltransferases Gcn5 and Esa1 Regulate Occupancy of RSC to Maintain Nucleosome-Depleted Regions and Promote RSC Recruitment to Coding Regions Genome-Wide in .
Biernat E, Verma M, Werick M … +3 more , Khan U, Joseph S, Govind CK
Mol Cell Biol · 2025 · PMID 40958614 · Full text
Chromatin remodelers are important for maintaining chromatin structure and regulating gene expression. In this study, we investigated the roles of histone acetyltransferases (HATs) Gcn5 and Esa1 in regulating RSC and his...
Chromatin remodelers are important for maintaining chromatin structure and regulating gene expression. In this study, we investigated the roles of histone acetyltransferases (HATs) Gcn5 and Esa1 in regulating RSC and histone occupancy on chromatin, as well as their impact on transcription across the genome. Our findings reveal distinct effects of HATs on RSC occupancy in promoters and ORFs. The lack of HATs leads to the accumulation of RSC, and it was greater in nucleosome-depleted regions (NDRs) containing fragile nucleosomes (FNs), relative to other NDRs. The increased RSC NDR-binding was greater in Esa1-deficient cells than in those lacking Gcn5. The increased RSC binding was not seen in cells lacking the H3 or H4 tails. The mutants also led to significant increases in histone occupancies around the NDRs genome-wide. Overall, the data suggest that hypoacetylated tails may recruit RSC to NDRs, especially to FN-containing NDRs, and that subsequent histone acetylation enhances histone eviction. The HAT mutants also exhibited reduced recruitment of TBP and Pol II. In contrast to the promoters, RSC occupancies were significantly reduced in transcribed ORFs in the HAT mutants. Thus, our data implicate HATs and RSC in maintaining NDRs, regulating chromatin structure, and promoting transcription.
PARP1-Dependent and Independent Pathways for Resolution of Trapped Topoisomerase I Covalent Complexes.
Das BB, Chowdhury B, Das S … +1 more , Banerjee A
Mol Cell Biol · 2025 · PMID 40955140 · Publisher ↗
Topoisomerase I (Top1) alleviates DNA supercoiling during replication and transcription, but its catalytic cycle can be hijacked by chemotherapeutic agents such as camptothecin (CPT), stabilizing Top1-DNA covalent comple...
Topoisomerase I (Top1) alleviates DNA supercoiling during replication and transcription, but its catalytic cycle can be hijacked by chemotherapeutic agents such as camptothecin (CPT), stabilizing Top1-DNA covalent complexes (Top1cc) that threaten genome integrity. Efficient resolution of these trapped intermediates is crucial to prevent replication stress, DNA breaks, and cell death. Poly (ADP-ribose) polymerase 1 (PARP1) is a key sensor of Top1cc, facilitating repair by recruiting tyrosyl-DNA phosphodiesterase 1 (TDP1) and modifying chromatin to promote lesion accessibility. Beyond this canonical pathway, emerging evidence highlights PARP1-independent mechanisms such as endo nucleolytic cleavage, proteolytic degradation of Top1 and replication-associated processing. Intriguingly, PARP1 appears to act as a molecular switch between TDP1 and the endonuclease pathway for the repair of Top1cc. This review highlights mechanisms of PARP1-dependent and -independent Top1cc repair pathways, their interplay and redundancy, and how their targeting can enhance Top1-based cancer therapies and overcome resistance.
Acyl-CoA Reductase Deficiency Impairs Ether Lipid Production and Hypomyelination in Mouse Brains.
Takahashi T, Otsuka K, Sassa T … +1 more , Kihara A
Mol Cell Biol · 2025 · PMID 40931707 · Publisher ↗
Mammalian cell membranes contain ether lipids, which include an alkyl chain derived from a fatty alcohol that is produced by fatty acyl-CoA reductases (FARs). There are two mammalian FAR genes, and , and mutations in c...
Mammalian cell membranes contain ether lipids, which include an alkyl chain derived from a fatty alcohol that is produced by fatty acyl-CoA reductases (FARs). There are two mammalian FAR genes, and , and mutations in cause the peroxisomal fatty acyl-CoA reductase 1 disorder (PFCRD), which is accompanied by various symptoms, including neurological disorders. To date, the contributions of and to brain ether lipid production and the molecular mechanism of PFCRD have remained unknown. To investigate these, we analyzed knockout (KO) mice of and . In the brain, the expression levels of were higher than those of , and was widely expressed. Lipidomic analyses showed that the quantity of ether lipids ethanolamine-plasmalogens was reduced in KO mice, with a complementary increase in diacyl-type phosphatidylethanolamines, but not in KO mice. Electron microscope analysis of the corpus callosum revealed reductions in the percentage of myelinated axons and myelin thickness in KO mice relative to WT mice. In conclusion, FAR1 is the major FAR isozyme involved in ether lipid synthesis in the brain, and its deficiency causes hypomyelination. We speculate that this hypomyelination is one of the causes of the neurological symptoms of PFCRD.
Immune Regulation of Itaconate and Its Derivatives in Liver Diseases.
Ge T, Zhang Y
Mol Cell Biol · 2025 · PMID 40928055 · Publisher ↗
Over the past few decades, liver disease has emerged as one of the leading causes of death worldwide. Liver injury is frequently associated with infections, alcohol consumption, or obesity, which trigger hepatic inflamma...
Over the past few decades, liver disease has emerged as one of the leading causes of death worldwide. Liver injury is frequently associated with infections, alcohol consumption, or obesity, which trigger hepatic inflammation and ultimately lead to progressive fibrosis and carcinoma. Although various cell populations contribute to inflammatory and fibrogenic processes in the liver, macrophages serve as a pivotal mediator. Hepatic macrophages exhibit substantial heterogeneity and perform diverse functions that depend on the pathological microenvironment. The immune response gene 1 (IRG1), a critical metabolic regulatory gene, encodes the mitochondrial enzyme aconitate decarboxylase 1 (ACOD1), which influences macrophage functional polarization by promoting the synthesis of itaconate, a metabolite produced via a side pathway of the tricarboxylic acid (TCA) cycle. Increasing evidence indicates that itaconate and its derivatives exert immunomodulatory effects in processes such as oxidative stress, viral infection, inflammation, tumorigenesis, and wound healing, thereby demonstrating significant potential for treating liver disorders. In this review, we summarize the roles of itaconate and its derivatives in liver diseases and their underlying mechanisms, thereby providing insights into the therapeutic potential of targeting macrophages.
Molecular Insights into the Pathophysiology of Dysregulated Erythropoiesis: The Crucial Role of Iron Homeostasis.
Fujiwara T, Harigae H
Mol Cell Biol · 2025 · PMID 40928051 · Publisher ↗
Erythropoiesis, i.e., process of red blood cell (RBC) production, is highly dependent on iron, with 60-70% of the total body iron incorporated into hemoglobin. Iron homeostasis is tightly regulated, given that both iron...
Erythropoiesis, i.e., process of red blood cell (RBC) production, is highly dependent on iron, with 60-70% of the total body iron incorporated into hemoglobin. Iron homeostasis is tightly regulated, given that both iron overload and deficiency can impair RBC development and function. Iron-loading anemias, such as sideroblastic anemia and thalassemia, are associated with ineffective erythropoiesis and systemic iron overload. Recent studies also highlight the role of ferroptosis, i.e., iron-dependent cell death, in erythroid failure under conditions of iron overload. Transcriptional repressor BTB and CNC homology 1 (BACH1), which is regulated by intracellular heme, is a potential key mediator of ferroptosis. In iron deficiency, limited iron availability impairs heme and globin biosynthesis, mitochondrial function, and erythropoietin responsiveness, while also inducing widespread changes in gene expression through DNA methylation, all of which contribute to dysregulated erythropoiesis. Under iron deficiency, BACH1 plays a critical role in maintaining the balance between heme and globin by suppressing globin gene expression, thereby preventing the aggregation of toxic non-heme globin. This review summarizes the current understanding of the mechanisms by which iron imbalance contributes to erythropoietic failure and highlights BACH1 as a potential integrative regulator in the pathophysiology of anemia in both iron-overload and iron-deficient states.
Causes, Consequences and Challenges of Intron Retention in lncRNAs.
Kumar M, Grammatikakis I
Mol Cell Biol · 2025 · PMID 40776630 · Publisher ↗
Alternative splicing is a major player in post-transcriptional gene regulation leading to transcript variant and protein isoform diversity. Intron retention (IR) is a type of alternative splicing resulting in inclusion o...
Alternative splicing is a major player in post-transcriptional gene regulation leading to transcript variant and protein isoform diversity. Intron retention (IR) is a type of alternative splicing resulting in inclusion of sequences in mature RNA which can significantly affect RNA stability, localization, and function. Although IR has not been extensively investigated, emerging evidence suggests that it plays a crucial role in gene expression regulation. Compared to messenger RNAs (mRNAs) derived by protein coding genes, long non-coding RNAs (lncRNAs) show inefficient splicing, more diverse alternative splicing patterns, and higher rates of IR. However, the consequences of IR in lncRNA function are much less straightforward with several intrinsic challenges influencing this phenomenon. In this review, we summarize the causes and consequences of IR in lncRNAs, how they differ from mRNAs, the challenges that lie in studying IR in lncRNAs, and the necessary steps for further investigation.
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