LMO7-mediated POLR2A degradation promotes cellular senescence through the MDM4/p53/p21 axisDownload PDF Download PDF ArticleOpen accessPublished: 28 March 2026Chutong Lai1,2,Wen Fu1,2,Jiaxin Liu1,2,Shuai Hou ORCID: orcid.org/0000-0001-5274-52641,2,Jinsong Yan ORCID: orcid.org/0000-0003-4109-26023 &…Haixin Lei ORCID: orcid.org/0000-0003-2445-81311,2,4 Cell Death & Disease , Article number: (2026) Cite this article We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.SubjectsSenescenceTranscriptionUbiquitylationAbstractAs the largest subunit of RNA polymerase II, POLR2A plays an irreplaceable role in gene expression, with the regulation of its own expression and physiological function having attracted widespread attention. Here we report POLR2A as a critical guardian against cellular senescence. A significant decline in POLR2A expression was observed in senescent cells and certain tissues of aging mice. Whereas its depletion dramatically induced cellular senescence, conversely, activating endogenous POLR2A expression in senescent cells using CRISPRa technology alleviated the senescent phenotype. We further demonstrated that POLR2A-induced senescence is p53-dependent, as evidenced by the activation of the p53/p21 pathway upon POLR2A knockdown and the rescue of the senescence phenotype following co-depletion of POLR2A and p53. Bioinformatic analysis on RNA-seq data from POLR2A depletion and replicative senescent cells led to the identification of MDM4 as the key mediator of p53 upregulation following POLR2A knockdown. Most intriguingly, immunoprecipitation assay further revealed that the E3 ligase LMO7 was recruited to POLR2A to promote the ubiquitination and proteasomal degradation of POLR2A under cellular senescence. Depletion of LMO7 abolished the ubiquitination and reduction of POLR2A in H₂O₂-induced senescent cells. Taken together, we concluded that the LMO7-induced POLR2A degradation drived cellular senescence through the MDM4/p53/p21 axis.Data availabilityThe data that support this study are available from the corresponding author upon request. The raw sequence data reported in this paper have been deposited in the Genome Sequence Archive in National Genomics Data Center[39], China National Center for Bioinformation / Beijing Institute of Genomics, Chinese Academy of Sciences (GSA-Human: HRA013617) that are publicly accessible at https://ngdc.cncb.ac.cn/gsa-human/browse/HRA013617.ReferencesVervoort SJ, Devlin JR, Kwiatkowski N, Teng M, Gray NS, Johnstone RW. 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The GSA family in 2025: a broadened sharing platform for multi-omics and multimodal data. Genom Proteom Bioinform. 2025;23:qzaf072.Google Scholar Download referencesAcknowledgementsThis work is sponsored by General Project of the Educational Department of Liaoning Province (LJKMZ20221255 and LJ212510161042 to S.H.), General Project of the Department of Science and Technology of Liaoning Province (2024-MSLH-111 to SH), National Natural Science Foundation of China (32171290 to HL), Research Platform Construction Project of the Educational Department of Liaoning Province (LJ232510161002 to H.L.), and Interdisciplinary Research Cooperation Project Team Funding of Dalian Medical University [JCHZ2023008 to HL]. We thank Dr Juan Shi at Institute of Basic Medical Sciences of Chinese Academy of Medical Sciences for providing pMSCV-LTR-dCas9-VP64-BFP and pSLQ1651-sgTelomere (F + E) plasmids. We thank Biorender for providing support with the graphical abstract and model diagram.Author informationAuthors and AffiliationsInstitute of Cancer Stem Cell, Dalian Medical University, Dalian, PR ChinaChutong Lai, Wen Fu, Jiaxin Liu, Shuai Hou & Haixin LeiLiaoning Provincial Key Laboratory of Nucleic Acids Biology, Dalian Medical University, Dalian, PR ChinaChutong Lai, Wen Fu, Jiaxin Liu, Shuai Hou & Haixin LeiDepartment of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Trans-plantation, The Second Hospital of Dalian Medical University, Dalian, PR ChinaJinsong YanCollege of Basic Medical Sciences, Hainan Medical University, Haikou, PR ChinaHaixin LeiAuthorsChutong LaiView author publicationsSearch author on:PubMed Google ScholarWen FuView author publicationsSearch author on:PubMed Google ScholarJiaxin LiuView author publicationsSearch author on:PubMed Google ScholarShuai HouView author publicationsSearch author on:PubMed Google ScholarJinsong YanView author publicationsSearch author on:PubMed Google ScholarHaixin LeiView author publicationsSearch author on:PubMed Google ScholarContributionsChutong Lai: Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – original draft. Wen Fu: Formal analysis, Resources. Jiaxin Liu: Data curation, Formal analysis, Resources. Shuai Hou: Conceptualization, Funding acquisition, Methodology, Project administration, Supervision, Writing – review & editing. Jinsong Yan: Funding acquisition, Project administration, Writing – review & editing. Haixin Lei: Conceptualization, Funding acquisition, Methodology, Project administration, Supervision, Writing – review & editing.Corresponding authorsCorrespondence to Shuai Hou, Jinsong Yan or Haixin Lei.Ethics declarationsCompeting interestsThe authors declare no competing interestsEthicsThe animal experimental protocol of this study was reviewed and approved by the Animal Ethics Committee of Dalian Medical University (Approval No.: AEE22115). The experiment was conducted in strict compliance with animal ethics standards to minimize animal suffering and ensure the scientific validity of the study.Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Edited by Dr Francesca BernassolaSupplementary informationclean version of Supplementary Figure legends (download DOCX )Supplemental-Figure 1 (download TIF )Supplemental-Figure 2 (download TIF )Supplemental-Figure 3 (download TIF )Supplemental-Figure 4 (download TIF )Supplemental-Figure 5 (download TIF )Supplemental-Figure 6 (download TIF )Table S1 (download XLSX )Table S2 (download XLSX )Table S3 (download XLSX )Table S4 (download XLSX )Table S5 (download XLSX )Table S6 (download XLSX )Table S7 (download XLSX )Original Data (download PDF )Rights and permissionsOpen Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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