The TP53-activated E3 ligase RNF144B is a tumour suppressor that prevents genomic instability

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• dc.contributor.author Abad Cortel, Etna
• dc.contributor.author Sandoz, Jérémy
• dc.contributor.author Romero, Gerard
• dc.contributor.author Zadra, Ivan
• dc.contributor.author Urgel i Solas, Júlia
• dc.contributor.author Borredat, Pablo
• dc.contributor.author Kourtis, Savvas
• dc.contributor.author Ortet Cortada, Laura
• dc.contributor.author Martínez, Carlos
• dc.contributor.author Weghorn, Donate
• dc.contributor.author Sdelci, Sara
• dc.contributor.author Janic, Ana
• dc.date.accessioned 2024-06-13T06:21:48Z
• dc.date.available 2024-06-13T06:21:48Z
• dc.date.issued 2024
• dc.description.abstract Background: TP53, the most frequently mutated gene in human cancers, orchestrates a complex transcriptional program crucial for cancer prevention. While certain TP53-dependent genes have been extensively studied, others, like the recently identified RNF144B, remained poorly understood. This E3 ubiquitin ligase has shown potent tumor suppressor activity in murine Eμ Myc-driven lymphoma, emphasizing its significance in the TP53 network. However, little is known about its targets and its role in cancer development, requiring further exploration. In this work, we investigate RNF144B's impact on tumor suppression beyond the hematopoietic compartment in human cancers. Methods: Employing TP53 wild-type cells, we generated models lacking RNF144B in both non-transformed and cancerous cells of human and mouse origin. By using proteomics, transcriptomics, and functional analysis, we assessed RNF144B's impact in cellular proliferation and transformation. Through in vitro and in vivo experiments, we explored proliferation, DNA repair, cell cycle control, mitotic progression, and treatment resistance. Findings were contrasted with clinical datasets and bioinformatics analysis. Results: Our research underscores RNF144B's pivotal role as a tumor suppressor, particularly in lung adenocarcinoma. In both human and mouse oncogene-expressing cells, RNF144B deficiency heightened cellular proliferation and transformation. Proteomic and transcriptomic analysis revealed RNF144B's novel function in mediating protein degradation associated with cell cycle progression, DNA damage response and genomic stability. RNF144B deficiency induced chromosomal instability, mitotic defects, and correlated with elevated aneuploidy and worse prognosis in human tumors. Furthermore, RNF144B-deficient lung adenocarcinoma cells exhibited resistance to cell cycle inhibitors that induce chromosomal instability. Conclusions: Supported by clinical data, our study suggests that RNF144B plays a pivotal role in maintaining genomic stability during tumor suppression.
• dc.description.sponsorship This work was supported by grants and fellowships from the Spanish Ministry of Science and Development Grant to A.J. (PID2021-127710OB-I00) and “La Caixa” foundation (51110009). A.J. is supported by Ramon y Cajal Research Fellowship (RYC2018-025244-I). I.Z. is funded by an AECC Postdoctoral Fellowship (POSTD234858ZADR), and J.U. by La Caixa PhD Scholarship (LCF/BQ/DR22/11950019). This work was made possible through the “Unidad de Excelencia María de Maeztu'' funded by the MCIN and AEI (CEX2018-000792-M).
• dc.format.mimetype application/pdf
• dc.identifier.citation Abad E, Sandoz J, Romero G, Zadra I, Urgel-Solas J, Borredat P, et al. The TP53-activated E3 ligase RNF144B is a tumour suppressor that prevents genomic instability. J Exp Clin Cancer Res. 2024 Apr 29;43(1):127. DOI: 10.1186/s13046-024-03045-4
• dc.identifier.doi http://dx.doi.org/10.1186/s13046-024-03045-4
• dc.identifier.issn 0392-9078
• dc.identifier.uri http://hdl.handle.net/10230/60449
• dc.language.iso eng
• dc.publisher BioMed Central
• dc.relation.ispartof J Exp Clin Cancer Res. 2024 Apr 29;43(1):127
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-127710OB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/CEX2018-000792-M
• dc.rights © The Author(s) 2024. Open 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. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Aneuploidy
• dc.subject.keyword Cancer
• dc.subject.keyword Genomic instability
• dc.subject.keyword Tumor suppressor
• dc.title The TP53-activated E3 ligase RNF144B is a tumour suppressor that prevents genomic instability
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion