Methylation of the central transcriptional regulator KLF4 by PRMT5 is required for DNA end resection and recombination
| Autor: | Javier Ramón, Daniel Gómez-Cabello, Cristina Cepeda-García, María S. Domínguez-Sánchez, Cintia Checa-Rodríguez, Ana López-Saavedra, Fernando R. Balestra, Pablo Huertas |
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| Přispěvatelé: | Ministerio de Economía y Competitividad (España), Universidad de Sevilla, Junta de Andalucía |
| Rok vydání: | 2020 |
| Předmět: |
Protein-Arginine N-Methyltransferases
DNA End-Joining Repair DNA end resection DNA damage DNA repair Kruppel-Like Transcription Factors Cellular homeostasis Biology Methylation Biochemistry Kruppel-Like Factor 4 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine stomatognathic system Downregulation and upregulation Cell Line Tumor Humans DNA Breaks Double-Stranded Molecular Biology 030304 developmental biology 0303 health sciences Recombinational DNA Repair Epistasis Genetic DNA Cell Biology KLF4 Recombination Cell biology Gene Expression Regulation chemistry 030220 oncology & carcinogenesis embryonic structures PRMT5 sense organs Homologous recombination Protein Processing Post-Translational Reprogramming |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| Popis: | Cell fitness and survival upon exposure to DNA damage depends on the repair of DNA lesions. Interestingly, cellular identity does affect and finetunes such response, although the molecular basis of such differences between tissues and cell types is not well understood. Thus, a possibility is that DNA repair itself is controlled by the mechanisms that govern cell identity. Here we show that the KLF4, involved in cellular homeostasis, proliferation, cell reprogramming and cancer development, directly regulates resection and homologous recombination proficiency. Indeed, resection efficiency follows KLF4 protein levels, i.e. decreases upon KLF4 downregulation and increases when is overexpressed. Moreover, KLF4 role in resection requires its methylation by the methyl-transferase PRMT5. Thus, PRMT5 depletion not only mimics KLF4 downregulation, but also showed an epistatic genetic relationship. Our data support a model in which the methylation of KLF4 by PRMT5 is a priming event required to license DNA resection and homologous recombination. This work was funded by R+D+I grants from the Spanish Ministry of Economy and Competitivity (SAF2013-43255-P, SAF2016-74855-P). FR-B is funded by the University of Sevillathrough a postdoctoral contract of the V PPIT-US. CABIMER is supported by the regional government of Andalucia (Junta de Andalucía). |
| Databáze: | OpenAIRE |
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