Journal of Biological Chemistry最新文献

{"title":"VRK1 regulates SRRM2 phosphorylation to promote the splicing of transcripts encoding DNA damage repair factors","authors":"Jinghan Rong, Xiaochun Yu","doi":"10.1016/j.jbc.2026.113669","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113669","url":null,"abstract":"Vaccinia-related kinase 1 (VRK1) is a nuclear serine/threonine kinase that contributes to genome stability through the phosphorylation of diverse substrates. VRK1 is frequently upregulated in multiple malignancies. Although its function as a chromatin kinase has been extensively characterized, its potential role in RNA processing remains largely unexplored. Using label-free quantitative phosphoproteomics, we identified the splicing scaffold protein serine/arginine repetitive matrix protein 2 (SRRM2) as a high-confidence VRK1-dependent phosphorylation target. We show that VRK1-dependent SRRM2 phosphorylation is required for efficient alternative splicing of DNA damage response (DDR)-related transcripts and contributes to cellular resistance to genotoxic stress. Collectively, this study reveals that VRK1 supports DDR-related splicing by regulating SRRM2 phosphorylation, providing a novel molecular mechanism by which VRK1 contributes to the DNA damage response.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"26 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149236138","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":"Recurring RNA motifs: from A-minor to ribose zipper","authors":"Matthew V. Law, Daniil Kiliushik, Emma J. Zablonski, Jermaine L. Jenkins, Joseph E. Wedekind","doi":"10.1016/j.jbc.2026.113668","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113668","url":null,"abstract":"The twenty-first century has been called the ‘century of RNA’. This name not only reflects the many recently discovered functional roles of RNA in biology but also the many new experimental RNA structures determined in this timeframe, which includes ribosomes, small ribozymes, self-splicing introns, spliceosomes, metabolite-sensing riboswitches, viral RNAs, and ornate large extremophilic RNAs, to name a few. In addition to zipping itself up via base pairing to form a complementary, DNA-like double helix, single-stranded RNA folds back on itself, producing many noncanonical interactions that are integral to its biological activity. Although the number of unique, experimentally determined RNA structures still lags far behind the number of proteins — existing in a so-called “structural dark matter” universe — a sufficient number of structures are known to identify folds and interaction themes that are frequently repeated. Here several common, recurring RNA motifs are presented for the non-specialist. An emphasis is placed on defining sequences or exemplar structures of each motif, close-packing and hydrogen-bonding attributes, classification (Leontis-Westhof) nomenclature, and examples of where the motif is found in nature. This atlas represents a foundation to understand how combinations of motifs lead to elegant hierarchical RNA tertiary and quaternary folds whose diverse forms impart distinct functions.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"4 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149236140","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":"Sialic Acids: From Biosynthesis and Molecular Recognition to Disease and Therapy","authors":"Susan Bellis, Vladislav Panin","doi":"10.1016/j.jbc.2026.113688","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113688","url":null,"abstract":"","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"8 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149236137","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":"Characterization of NfnAB of Heliomicrobium modesticaldum, an Electron Bifurcating Enzyme Involved in Phototrophic Energy Conversion","authors":"Karim A. Walters, Kathryn R. Tomah, Vivian Pham, Patricia Baker, John H. Golbeck, Kevin E. Redding","doi":"10.1016/j.jbc.2026.113662","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113662","url":null,"abstract":"Analysis of the <ce:italic>Heliomicrobium modesticaldum</ce:italic> genome suggests that polypeptides encoded by the genes HM1_0289 and HM1_0290 correspond to the NfnA and NfnB subunits of an NAD-dependent ferredoxin:NADP<ce:sup loc=\"post\">+</ce:sup> oxidoreductase electron-bifurcating enzyme, NfnAB, similar to that found in archea and anaerobic bacteria. NfnA contains a flavin cofactor and a [2Fe-2S] cluster, whose potential has not been previously measured. It exists in two spectroscopically distinct populations: a major species with <ce:italic>E</ce:italic><ce:inf loc=\"post\"><ce:italic>m</ce:italic></ce:inf> ≈ -364 mV and a minor species with <ce:italic>E</ce:italic><ce:inf loc=\"post\"><ce:italic>m</ce:italic></ce:inf> ≈ -423 mV. NfnB contains two [4Fe-4S] clusters, one with <ce:italic>E</ce:italic><ce:inf loc=\"post\"><ce:italic>m</ce:italic></ce:inf> ≈ -430 mV and the other with <ce:italic>E</ce:italic><ce:inf loc=\"post\"><ce:italic>m</ce:italic></ce:inf> ≤ -650 mV. Individually, NfnA and NfnB were selective for oxidation of NADH and NADPH respectively. Together, the NfnAB holoenzyme catalyzes the electron bifurcation reaction (2 Fd<ce:sup loc=\"post\">ox</ce:sup> + NAD<ce:sup loc=\"post\">+</ce:sup> + 2 NADPH ⇆ 2 Fd<ce:sup loc=\"post\">red</ce:sup> + NADH + 2 NADP<ce:sup loc=\"post\">+</ce:sup>), where Fd corresponds to a heliobacterial dicluster ferredoxin. In the absence of a traditional FNR, heliobacteria may use NfnAB in electron confurcation to accomplish two functions: light-driven cyclic electron transport and transfer of reducing equivalents from NADH to NADP<ce:sup loc=\"post\">+</ce:sup>. Deletion of the <ce:italic>nfnAB</ce:italic> genes resulted in mutants that were viable in all growth modes tested, but <ce:italic>in vivo</ce:italic> spectroscopic analysis indicated that light-driven electron transport was limited in the absence of NfnAB. As heliobacteria are considered descendants of a clostridial-type bacterium that received the genes for phototrophy via lateral gene transfer, NfnAB may be an archaic protein that was re-purposed for use in phototrophic energy conversion, a function not previously reported for this enzyme.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"22 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149236142","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":"Temperature-Dependent N2 Reduction and Energy Demands of Mo- and V-Nitrogenases","authors":"Derek F. Harris, Betül Kaçar, Lance C. Seefeldt","doi":"10.1016/j.jbc.2026.113663","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113663","url":null,"abstract":"Nitrogenase catalyzes the ATP-dependent reduction of dinitrogen to ammonia, a key step in the global nitrogen cycle. The Mo- and V-dependent nitrogenase isozymes are expressed under different environmental conditions, including temperature, yet little is known about how their catalytic behavior changes with temperature. Here, we examine the temperature dependence of total electron flux, electron partitioning into the products NH<ce:inf loc=\"post\">3</ce:inf> and H<ce:inf loc=\"post\">2</ce:inf>, and estimate ATP energy costs per N<ce:inf loc=\"post\">2</ce:inf> fixed for purified Mo- and V-nitrogenases from <ce:italic>Azotobacter vinelandii</ce:italic> over a 10-50 ˚C temperature range. Both isozymes exhibit similar temperature-dependent scaling of total electron flux to all products across the temperature range, but with significantly different distributions of electrons to H<ce:inf loc=\"post\">2</ce:inf> or NH<ce:inf loc=\"post\">3</ce:inf> formation. As temperature increases, V-nitrogenase diverts an increasing fraction of electron flux into H<ce:inf loc=\"post\">2</ce:inf> formation, whereas Mo-nitrogenase maintains a nearly constant electron partitioning to N<ce:inf loc=\"post\">2</ce:inf> reduction. The estimated ATP molecules hydrolyzed per N<ce:inf loc=\"post\">2</ce:inf> reduced change little for the Mo-nitrogenase across this temperature range, but rises significantly for the V-nitrogenase with increasing temperature, reaching over 200 ATP per N<ce:inf loc=\"post\">2</ce:inf> fixed at 50 ˚C. These results demonstrate that, in <ce:italic>A. vinelandii</ce:italic>, the Mo- and V-nitrogenases exhibit significantly different responses of electron partitioning to products and ATP hydrolyzed per N<ce:inf loc=\"post\">2</ce:inf> reduced to changes in temperature. These findings suggest environmental conditions under which each isozyme would be optimal, with V- and Mo-nitrogenase both being favorable at low temperatures and Mo-nitrogenase being the only energetically reasonable enzyme at higher temperatures.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"38 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149236141","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":"Mapping of pikachurin heparan sulfate modification to a region dispensable for synaptic localization in photoreceptors","authors":"Robyn V. McGowan, Faiyaz A.K. Abid, Melina A. Agosto","doi":"10.1016/j.jbc.2026.113632","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113632","url":null,"abstract":"Rod and cone photoreceptors (PRs) are specialized neurons that detect light, then transmit information to bipolar cells at synapses in the outer plexiform layer of the retina. Pikachurin (PIKA) is a multi-domain heparan sulfate (HS) proteoglycan expressed in PRs. It is secreted into the synaptic cleft, where it binds to presynaptic dystroglycan, postsynaptic orphan receptor GPR179, and postsynaptic adhesion molecule LRRTM4. Knockout of PIKA results in ultrastructural and functional defects at rod synapses. However, the role of HS in PIKA function at synapses is unknown. Using a panel of deletion and truncation mutants expressed in heterologous cells, we determined that a.a. 240-342, a region of unknown function between the last fibronectin III domain and the first EGF-like domain, is necessary and sufficient for PIKA HS modification. Site-directed mutagenesis of S244, identified as a likely candidate based on neighboring sequences, abolished HS modification, indicating that this residue is the sole HS attachment site. Deletion of the 240-342 region or mutation of S244 also abolished co-immunoprecipitation of LRRTM4, consistent with the previously reported HS-dependent binding. To assess requirements for synaptic localization, PIKA mutants were expressed in mouse rods. Deletion of the HS-containing region or the fibronectin III domains did not prevent localization at rod presynapses. In contrast, deletion of the first EGF-like and laminin G domains severely impaired localization, suggesting an important role for these domains in mediating trafficking or synaptic enrichment.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"23 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149236154","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":"Demand for de novo serine biosynthesis in C. elegans embryos is buffered by the glycine cleavage system and maternal diet","authors":"Joanna Zaino, Amanda Anderson, Omar Rachidi Alaoui, Olga Ponomarova","doi":"10.1016/j.jbc.2026.113667","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113667","url":null,"abstract":"Metabolic network plasticity helps organisms survive change, including dietary fluctuations, transitions between developmental stages and genetic perturbations. To maintain a robust supply of resources under these conditions, metabolic networks must rebalance flux across individual pathways. However, how pathways coordinate their activity to support homeostasis remains poorly understood. Here, we use metabolomics, dietary supplementation, and genetic screening to investigate how the network compensates for the loss of phosphoglycerate dehydrogenase PHDH-1, the rate-limiting enzyme in serine biosynthesis. We find that PHDH-1 dysfunction causes developmental delay and substantially alters the metabolome of <ce:italic>C. elegans</ce:italic> embryos, but not that of adult animals. Despite these perturbations, <ce:italic>Δphdh-1</ce:italic> mutant embryos remain viable through the compensatory activity of enzymes that we identified through a genetic interaction screen. The identified PHDH-1 interactions span the metabolic network and are alleviated by maternal serine supplementation, revealing wide-ranging functional links between serine metabolism and distant pathways. We further demonstrate how the joint action of PHDH-1, the glycine cleavage system and the maternal diet sustains embryonic one-carbon metabolism. Overall, our results reveal how metabolic networks buffer the supply of one-carbon units to compensate for enzyme dysfunction and support robust development.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"166 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149236139","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":"RNA polymerase I inhibitor BMH-21 promotes mutant p53 reactivation through nuclear zinc mobilization","authors":"Jonathan Y. Chung, Venkatesh Lottipalli, Stewart N. Loh, Bruce A. Knutson","doi":"10.1016/j.jbc.2026.113660","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113660","url":null,"abstract":"RNA polymerase I (Pol I) inhibitors activate stress signaling pathways with therapeutic potential in cancer, yet the consequences of Pol I inhibition in p53-mutant tumors remain incompletely understood. Here, we compared the interactions of the Pol I inhibitors CX-5461 and BMH-21 with the p53 reactivators APR-246 and ZMC-1 in p53<ce:sup loc=\"post\">R175H</ce:sup> breast cancer cells. Whereas CX-5461 synergized with p53 reactivators, BMH-21 antagonized these combinations. Unexpectedly, BMH-21 alone restored mutant p53 transcriptional activity and promoted a shift toward a wild-type–like p53 conformation. Mechanistically, BMH-21 increased nuclear labile zinc levels, correlated with degradation of the Pol I catalytic subunit RPA194, and induced stabilization of the zinc-responsive stress factor NRF2. Limiting RPA194 degradation through FBXL14 depletion reduced both nuclear zinc flux and p53-dependent transcriptional activity, supporting a functional link between Pol I destabilization, zinc mobilization, and mutant p53 reactivation. Inhibition of p53 signaling enhanced BMH-21 cytotoxicity, indicating that mutant p53 reactivation promotes a protective stress response rather than cell death. Together, these findings demonstrate that Pol I inhibitors are functionally distinct and identify a previously unrecognized link between Pol I inhibition, zinc homeostasis, and mutant p53 regulation.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"12 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149236153","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":"Hat1 Orchestrates Heterochromatin Structure by Regulating Localization of H3K9 Methyltransferases.","authors":"Caden J Martin, Liudmila V Popova, Prabakaran Nagarajan, Elizabeth A Oser, Callie M Lovejoy, Benjamin D Sunkel, Benjamin Z Stanton, Michael A Freitas, Mark R Parthun","doi":"10.1016/j.jbc.2026.113659","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113659","url":null,"abstract":"<p><p>Many regions of heterochromatin associate with the nuclear periphery and are known as Lamin-associated domains (LADs). Histone acetyltransferase 1 (Hat1) is a highly conserved enzyme which acetylates newly synthesized histone H4 on lysines 5 and 12 prior to deposition on chromatin. Hat1 is required to preserve chromatin accessibility within a subset of LADs called Hat1-dependent accessibility domains (HADs). Here we profile a diverse set of histone modifications in Hat1 KO and WT immortalized mouse embryonic fibroblasts (iMEFs) and find that Hat1 regulates diverse aspects of the structure of HADs and non-HAD LADs (nhLADS). In HADs, these changes include the conversion of H3K9me2 to H3K9me3. Analysis of H3K9-specific histone methyltransferases (HMTs) shows that Suv39h1 and Suv39h2 have distinct localization patterns, where only Suv39h2 localizes to LADs. G9a only localizes to LADs in regions enriched for H3K9me2. We find that Hat1 loss results in an altered localization of these HMTs in both HADs and nh LADs. There is a decrease in the levels of G9a with a concomitant increase in Suv39h2. These results suggest Hat1 functions to restrain the formation of a more strongly heterochromatic state and highlight a role for Hat1 as a regulator of heterochromatin structure.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113659"},"PeriodicalIF":4.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227795","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":"Hyperpolarization-activated cyclic nucleotide-gated channels preserve excitability in ON-bipolar cells after degeneration.","authors":"Jung Woong Chu, Bokeum Kang, Kyungmin Kim, Hyeonhee Roh, Uhtaek Oh, Hyungsup Kim, Yong Soo Park, Seok-Kyu Kwon, Maesoon Im, Min Soo Kim, Huan-Jun Lu, Gyu-Sang Hong","doi":"10.1016/j.jbc.2026.113657","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113657","url":null,"abstract":"<p><p>Retinal degeneration leads to extensive remodeling of inner retinal circuits following photoreceptor loss, but the intrinsic membrane properties of surviving bipolar cells remain incompletely understood. Here, we investigated the expression and functional contribution of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in ON-bipolar cells using the rd10 mouse model of retinitis pigmentosa. High-resolution fluorescence in situ hybridization showed no significant differences in Hcn1, Hcn2, and Hcn4 transcript levels between wild-type (WT) and rd10 bipolar cells. Whole-cell patch-clamp recordings detected hyperpolarization-activated inward currents consistent with I_h in both WT and rd10 ON-bipolar cells with no significant differences. In current-clamp recordings, the recovery of membrane potential following hyperpolarizing current pulses was significantly slowed by HCN channel blockers (ivabradine and ZD7288) in both genotypes. These findings indicate that HCN-sensitive conductances contribute to membrane potential recovery in ON-bipolar cells and remain detectable after photoreceptor degeneration.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113657"},"PeriodicalIF":4.0,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206917","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}