IUBMB Life最新文献

{"title":"Tinagl1 restores tamoxifen sensitivity and blocks fibronectin-induced EMT by simultaneously blocking the EGFR and β1-integrin/FAK signaling pathways in tamoxifen-resistant breast cancer cells","authors":"Jie Yuan,&nbsp;Li Yuan,&nbsp;Li Yang,&nbsp;Arunachalam Chinnathambi,&nbsp;Sulaiman Ali Alharbi,&nbsp;Jun Huang,&nbsp;Bei Wang,&nbsp;Shuqi Zhang,&nbsp;Changsheng Wei,&nbsp;Chengyu Luo","doi":"10.1002/iub.2940","DOIUrl":"10.1002/iub.2940","url":null,"abstract":"<p>Tamoxifen (TAM) is employed to treat premenopausal ER-positive breast cancer patients, but TAM resistance is the main reason affecting its efficacy. Thus, addressing TAM resistance is crucial for improving therapeutic outcomes. This study explored the potential role of Tinagl1, a secreted extracellular matrix protein, whose expression is compromised in TAM-resistant MCF-7 breast cancer cells (MCF-7R). We discovered that Tinagl1 plays a pivotal role in countering TAM resistance by inhibiting the EGFR and β1-integrin/focal adhesion kinase (FAK) signaling pathways, both of which are abnormally activated in MCF-7R cells and contribute to the resistance mechanism. Our data showed that the expression level of Tinagl1 in MCF-7R cells was lower compared to their wild-type counterparts, and TAM could further reduce Tinagl1 expression in MCF-7R cells, which was consistent with our microarray results. Moreover, Tinagl1 could restore the sensitivity of MCF-7R cells to TAM and inhibit the motility of MCF-7R cells by regulating epithelial-mesenchymal transition (EMT) in vitro and in vivo experiments. In addition, the level of Tinagl1 in TAM-resistant breast cancer samples was significantly lower than that in their matched primary tumors. Analysis of an online database further indicated that high Tinagl1 expression correlates with better recurrence-free survival (RFS), particularly in patients with ER-positive, HER2-negative breast cancer. Overall, this study positions Tinagl1 not only as a potential prognostic marker but also as a promising therapeutic target.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143005448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overexpression of RGPR-p117 reveals anticancer effects by regulating multiple signaling pathways in bone metastatic human breast cancer MDA-MB-231 cells","authors":"Masayoshi Yamaguchi,&nbsp;Tomiyasu Murata,&nbsp;Noriaki Shimokawa","doi":"10.1002/iub.2939","DOIUrl":"10.1002/iub.2939","url":null,"abstract":"<p>The role of RGPR-p117, a transcription factor, which binds to the TTGGC motif in the promoter region of the regucalcin gene, in cell regulation remains to be investigated. This study elucidated whether RGPR-p117 regulates the activity of triple-negative human breast cancer MDA-MB-231 cells in vitro. The wild-type and RGPR-p117-overexpressing cancer cells were cultured in DMEM supplemented with fetal bovine serum. RGPR-p117 overexpression suppressed colony formation and growth of cancer cells. Stimulatory effects of epidermal growth factor on cell growth were blocked by RGPR-p117 overexpression. Wild-type cell proliferation was repressed by cell cycle and intracellular signaling inhibitors. These effects were not potentiated in transfectants. Overexpressed RGPR-p117 protected cancer cells against apoptosis inducers. Mechanistic results showed that RGPR-p117 overexpression decreased the expression of Ras, PI3-kinase, Akt, mitogen-activated protein kinase, and mTOR, which are involved in cell growth, while it elevated the levels of the cancer cell suppressor p53, Rb, p21, and regucalcin. Overexpression of RGPR-p117 suppressed cancer cell migration and adhesion. Interestingly, osteoblastic MC3T3-E1 cells or macrophage RAW264.7 cells involved in the bone microenvironment were impaired by coculture with MDA-MB-231 cells. The effects of cancer cells were blocked by transfection. Coculture with conditioned medium obtained from breast cancer cells repressed proliferation and enhanced the death of osteoblastic cells and macrophages. A TNF-α signaling inhibitor blocked these effects. Thus, overexpressed RGPR-p117 was found to suppress the activity of breast cancer cells by regulating various signaling processes, providing new insight into cellular signaling regulation.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RETRACTION: Amp-Kinase Inhibitor Dorsomorphin Reduces the Proliferation and Migration Behavior of Colorectal Cancer Cells by Targeting the Akt/mTOR Pathway","authors":"","doi":"10.1002/iub.2941","DOIUrl":"10.1002/iub.2941","url":null,"abstract":"<p>RETRACTION: S. Ghanaatgar-Kasbi, F. Amerizadeh, F. Rahmani, S. M. Hassanian, M. Khazaei, G. A. Ferns and A. Avan, “Amp-Kinase Inhibitor Dorsomorphin Reduces the Proliferation and Migration Behavior of Colorectal Cancer Cells by Targeting the Akt/mTOR Pathway,” <i>IUBMB Life</i> 71, no. 12 (2019): 1929–1936, https://doi.org/10.1002/iub.2136.</p><p>The above article, published online on 30 July 2019 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Efstathios S. Gonos; International Union of Biochemistry and Molecular Biology; and Wiley Periodicals LLC. The retraction has been agreed following an investigation into concerns raised by a third party which revealed that the TBHP image and the Dorso 5μM image in Figure 3b contained an overlap with images published elsewhere by some of the same authors. In both instances of duplication, the images were used to represent different experimental conditions. Furthermore, the western blot in Figure 4D has been inappropriately edited and there is evidence that the bands have been spliced without clearly marking the splice sites. The authors provided an explanation and some data but this was not considered sufficient to address the concerns. As a result, the editors have lost confidence in the data presented and consider the conclusions substantially compromised. The authors disagree with the retraction.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/iub.2941","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simultaneous blockade of the CD73/EGFR axis inhibits tumor growth","authors":"Keivan Ardeshiri,&nbsp;Hadi Hassannia,&nbsp;Ghasem Ghalamfarsa,&nbsp;Hanieh Jafary,&nbsp;Farhad Jadidi","doi":"10.1002/iub.2933","DOIUrl":"10.1002/iub.2933","url":null,"abstract":"<p>Targeting the influencing factors in tumor growth and expansion in the tumor microenvironment is one of the key approaches to cancer immunotherapy. Various factors in the tumor microenvironment can in cooperation stimulate tumor growth, suppress anti-tumor immune responses, promote drug resistance, and ultimately enhance tumor recurrence. Therefore, due to the dependence and close cooperation of these axes, their combined targeting can have a greater effect compared to their individual targeting. Among the important factors affecting tumor growth in the tumor region, CD73 and EGFR play an important role in tumor growth by stimulating each other's expression and function. Therefore, we intended to use the nanocarriers that we had previously produced and characterized to deliver anti-CD73 and EGFR siRNAs to murine breast cancer 4T1 cells. Silencing CD73 and EGFR could significantly induce cell death in cancer cells. Downregulation of the CD73/EGFR axis also suppressed the migratory and proliferative potential of cancer cells. This therapeutic strategy also inhibited tumor growth in <i>in ovo</i> model. These findings imply that simultaneous targeting of CD73 and EGFR in breast cancer can be considered a novel immunotherapeutic approach that needs further investigation in future studies.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Keratinocyte exosomal LOC285194 ameliorates psoriasis by inhibiting the differentiation of CD4+T cells to Th17 cells through regulating miR-211-5p/SIRT1 axis","authors":"Jin Lin,&nbsp;Yi Cao,&nbsp;Lili Ma,&nbsp;Maocan Tao,&nbsp;Xiaohong Yang","doi":"10.1002/iub.2935","DOIUrl":"10.1002/iub.2935","url":null,"abstract":"<p>Keratinocytes exosome participates in the pathogenesis of psoriasis and exosomes always carry long non-coding RNAs (lncRNAs) into target cells to function as an essential immune regulator in psoriasis-related diseases. LncRNA LOC285194 is closely associated with the occurrence of psoriasis. However, whether keratinocyte exosomal LOC285194 participates in the process of psoriasis remains vague. Exosomes were authenticated by transmission electron microscope and nanoparticle tracking analysis (NTA). Relative gene expression was determined by reverse transcription-polymerase chain reaction (RT-PCR). Flow cytometry was used to monitor the proportion of immune cells. Fluorescence in situ hybridization was employed to determine the colocalization of lncRNA and miRNA. Keratinocyte exosomal LOC285194 was reduced in psoriasis patients and had a negative association with Th17 cell infiltration in psoriasis patients. LOC285194-downregulation contributed to the differentiation of CD4⁺T cells to Th17 cells. Cytokine cocktail treatment reduced LOC285194 expression in keratinocytes and keratinocyte exosome, subsequently promoted the differentiation of CD4⁺T cells to Th17 cells and Th17 cells-related molecular levels including IL-17A, IL-22 and TNF-α, which were notably abrogated by LOC285194-upregulation in keratinocytes. As a sponge of LOC285194, miR-211-5p inhibition induced the increase of Th17 cell proportion in CD4⁺T cells, while exosomes treatment isolated from cytokine cocktail-exposed keratinocytes further enhanced Th17 cell proportion, which were abolished by LOC285194 overexpressed-exosome treatment. Furthermore, silent information regulator 1 (SIRT1) mediated the regulation role of miR-211-5p on Th17 cell production. Combined with the imiquimod-induced psoriasis animal model, exosomes isolated from LOC285194-overexpressing keratinocytes relieved psoriasis symptom through regulating miR-211-5p/SIRT1 axis. LOC285194 upregulation in keratinocytes promoted the keratinocyte exosomal LOC285194, that could be absorbed by CD4⁺T cells, leading to the inhibition of Th17 cell differentiation through targeting miR-211-5p/SIRT1 axis. This study provides a novel molecular mechanism of Th17 cell accumulation-mediated psoriasis.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The therapeutic effects of induced pluripotent stem cell-derived mesenchymal stem cells on Parkinson's disease","authors":"Hao Ren,&nbsp;Yuwei Wang,&nbsp;Yingying Chen,&nbsp;Feilong Ma,&nbsp;Qing Shi,&nbsp;Zichen Wang,&nbsp;Yaoting Gui,&nbsp;Jianbo Liu,&nbsp;Huiru Tang","doi":"10.1002/iub.2936","DOIUrl":"10.1002/iub.2936","url":null,"abstract":"<p>Parkinson's disease (PD), characterized by progressive degeneration of dopaminergic neurons in substantia nigra, has no disease-modifying therapy. Mesenchymal stem cell (MSC) therapy has shown great promise as a disease-modifying solution for PD. Induced pluripotent stem cell-derived MSC (iMSC) not only has stronger neural repair function, but also helps solve the problem of MSC heterogeneity. So we evaluated the therapeutic effects of iMSCs on PD. iMSCs were administered by tail vein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD models of C57BL/6 mice. The results showed iMSCs increased body weights, inhibited the prolongation of latencies to descend in pole tests, the decrease of grip strength in grip strength tests and increase of open arm entries in elevated plus maze test, and showed a trend to alleviate striatal dopamine loss. They indicate iMSCs might improve functions partially by preserving striatal dopamine in PD. We for the first time (1) found that iMSC has therapeutic effects on PD; (2) tested specifically muscle strength in cell therapy for PD and found it increases muscle strength; (3) found cell therapy alleviated the increase of entries into the open arms in PD. It suggests iMSC is a promising candidate for clinical investigations and drug development for PD.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ketorolac disturbs proteasome functions and induces mitochondrial abnormality-associated apoptosis","authors":"Prashant Kumar,&nbsp;Sumit Kinger,&nbsp;Ankur Rakesh Dubey,&nbsp;Yuvraj Anandrao Jagtap,&nbsp;Akash Choudhary,&nbsp;Surojit Karmakar,&nbsp;Girdhari Lal,&nbsp;Amit Kumar,&nbsp;Sudipta Bhattacharyya,&nbsp;Krishna Mohan Poluri,&nbsp;Amit Mishra","doi":"10.1002/iub.2937","DOIUrl":"10.1002/iub.2937","url":null,"abstract":"<p>Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended to treat moderate-to-severe pain. Previous studies suggest that NSAIDs can suppress cellular proliferation and elevate apoptosis in different cancer cells. Ketorolac is an NSAID and can reduce the cancer cells' viability. However, molecular mechanisms by which Ketorolac can induce apoptosis and be helpful as an anti-tumor agent against carcinogenesis are unclear. Here, we observed treatment with Ketorolac disturbs proteasome functions, which induces aggregation of aberrant ubiquitinated proteins. Ketorolac exposure also induced the aggregation of expanded polyglutamine proteins, results cellular proteostasis disturbance. We found that the treatment of Ketorolac aggravates the accumulation of various cell cycle-linked proteins, which results in pro-apoptotic induction in cells. Ketorolac-mediated proteasome disturbance leads to mitochondrial abnormalities. Finally, we have observed that Ketorolac treatment depolarized mitochondrial membrane potential, released cytochrome <i>c</i> into cytoplasm, and induced apoptosis in cells, which could be due to proteasome functional depletion. Perhaps more in-depth research is required to understand the details of NSAID-based anti-proliferative molecular mechanisms that can elevate apoptosis in cancer cells and generate anti-tumor potential with the combination of putative cancer drugs.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142894287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ethical bioprospecting and microbial assessments for sustainable solutions to the AMR crisis","authors":"Kayla Cartledge,&nbsp;Francesca L. Short,&nbsp;Alex Hall,&nbsp;Karen Lambert,&nbsp;Michael J. McDonald,&nbsp;Trevor Lithgow","doi":"10.1002/iub.2931","DOIUrl":"10.1002/iub.2931","url":null,"abstract":"<p>Antimicrobial resistance (AMR) has been declared one of the top 10 global public health challenges of our age by the World Health Organization, and the World Bank describes AMR as a crisis affecting the finance, health, and agriculture sectors and a major threat to the attainment of Sustainable Development Goals. But what is AMR? It is a phenotype that evolves in microbes exposed to antimicrobial molecules and causes dangerous infections. This suggests that scientists and healthcare workers should be on the frontline in the search for sustainable solutions to AMR. Yet AMR is also a societal problem to be understood by everyone. This review aims to explore the need to address the problem of AMR through a coherent, international strategy with buy-in from all sectors of society. As reviewed here, the sustainable solutions to AMR will be driven by better understanding of AMR biology but will require more than this alone to succeed. Some advances on the horizon, such as the use of bacteriophage (phage) to treat AMR infections. However, many of the new technologies and new therapeutics to address AMR require access to biodiversity, where the custodians of that biodiversity—and the traditional knowledge required to access it—are needed as key partners in the scientific, clinical, biotechnological, and international ventures that would treat the problem of AMR and ultimately prevent its further evolution. Many of these advances will be built on microbial assessments to understand the extent of AMR in our environments and bioprospecting to identify microbes that may have beneficial uses. Genuine partnerships for access to this biodiversity and sharing of benefits accrued require a consideration of ethical practice and behavior. Behavior change is needed across all sectors of culturally diverse societies so that rapid deployment of solutions can be implemented for maximum effect against the impacts of AMR.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11668235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic features of lichen-associated black fungi","authors":"Victoria Keller,&nbsp;Anjuli Calchera,&nbsp;Jürgen Otte,&nbsp;Imke Schmitt","doi":"10.1002/iub.2934","DOIUrl":"10.1002/iub.2934","url":null,"abstract":"<p>Lichens are mutualistic associations consisting of a primary fungal host, and one to few primary phototrophic symbiont(s), usually a green alga and/or a cyanobacterium. They form complex thallus structures, which provide unique and stable habitats for many other microorganisms. Frequently isolated from lichens are the so-called black fungi, or black yeasts, which are mainly characterized by melanized cell walls and extremophilic lifestyles. It is presently unclear in which ways these fungi interact with other members of the lichen symbiosis. Genomic resources of lichen-associated black fungi are needed to better understand the physiological potential of these fungi and shed light on the complexity of the lichen consortium. Here, we present high-quality genomes of 14 black fungal lineages, isolated from lichens of the rock-dwelling genus <i>Umbilicaria.</i> Nine of the lineages belong to the Eurotiomycetes (Chaetothyriales), four to the Dothideomycetes, and one to the Arthoniomycetes, representing the first genome of a black fungus in this class. The PacBio-based assemblies are highly contiguous (5–42 contigs per genome, mean coverage of 79–502, N50 of 1.0–7.3 mega-base-pair (Mb), Benchmarking Universal Single-Copy Orthologs (BUSCO) completeness generally ≥95.4%). Most contigs are flanked by a telomere sequence, suggesting we achieved near chromosome-level assemblies. Genome sizes range between 26 and 44 Mb. Transcriptome-based annotations yielded ~11,000–18,000 genes per genome. We analyzed genome content with respect to repetitive elements, biosynthetic genes, and effector genes. Each genome contained a polyketide synthase gene related to the dihydroxynaphthalene-melanin pathway. This research provides insights into genome content and metabolic potential of these relatively unknown, but frequently encountered lichen associates.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11664114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human disease-causing missense genetic variants are enriched in the evolutionarily ancient domains of the cytosolic aminoacyl-tRNA synthetase proteins","authors":"Alexandra K. Turvey,&nbsp;André R. O. Cavalcanti","doi":"10.1002/iub.2932","DOIUrl":"10.1002/iub.2932","url":null,"abstract":"<p>All life depends on accurate and efficient protein synthesis. The aminoacyl-tRNA synthetases (aaRSs) are a family of proteins that play an essential role in protein translation, as they catalyze the esterification reaction that charges a transfer RNA (tRNA) with its cognate amino acid. However, new domains added to the aaRSs over the course of evolution in eukaryotes confer novel functions unrelated to protein translation. To date, damaging variants that affect aaRS-encoding genes have been linked to over 50 human diseases. In this study, we leverage the evolutionary history of the aaRS proteins to better understand the distribution of disease-causing missense variants in human cytosolic aaRSs. We hypothesized that disease-causing missense variants in human aaRSs were more likely to be located in the ancient domains of the aaRS, essential for the aminoacylation reaction, rather than in the evolutionarily more recent domains found in eukaryotes. We determined the locations of the modern and ancient domains in each aaRS protein found in humans. We then statistically assessed the positional conservation across each domain and examined the distribution of pathogenic and benign/unknown missense human genetic variants across these domains. We establish that pathogenic missense variants in the human aaRS proteins are enriched in the evolutionarily ancient domains while benign/unknown missense variants are enriched in the modern domains. In addition to defining the evolutionary history of human aaRS proteins through domain identification, we anticipate that this work will improve the ability to diagnose patients affected by damaging genetic variants in the aaRS protein family.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11664165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}