Antagonistic relationship of NuA4 with the Non-Homologous End-Joining machinery at DNA damage sites
| Autor: | Gaelle Bourriquen, Xue Cheng, Mohammed Altaf, Salar Ahmad, Jacques Côté, Vasileia Sapountzi, Valérie Côté |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
DNA End-Joining Repair DNA Repair RAD52 Gene Expression QH426-470 Biochemistry chemistry.chemical_compound 0302 clinical medicine Post-Translational Modification Amino Acids Genetics (clinical) Histone Acetyltransferases Regulation of gene expression 0303 health sciences Chromosome Biology Organic Compounds Monosaccharides Chemical Reactions Eukaryota Acetylation Cell cycle Chromatin Cell biology Nucleic acids Non-homologous end joining Chemistry Acetyltransferase Physical Sciences Epigenetics Basic Amino Acids Research Article Saccharomyces cerevisiae Proteins DNA repair DNA damage Carbohydrates Saccharomyces cerevisiae Biology Non-Homologous End Joining 03 medical and health sciences Genetics NuA4 histone acetyltransferase complex Molecular Biology Ecology Evolution Behavior and Systematics 030304 developmental biology Biology and life sciences Lysine Organic Chemistry fungi Organisms Fungi Chemical Compounds G1 Phase Proteins Galactose DNA Cell Biology Yeast enzymes and coenzymes (carbohydrates) chemistry Homologous recombination 030217 neurology & neurosurgery |
| Zdroj: | PLoS Genetics, Vol 17, Iss 9, p e1009816 (2021) PLoS Genetics |
| DOI: | 10.1101/2021.01.29.428810 |
| Popis: | The NuA4 histone acetyltransferase complex, apart from its known role in gene regulation, has also been directly implicated in the repair of DNA double-strand breaks (DSBs), favoring homologous recombination (HR) in S/G2 during the cell cycle. Here, we investigate the antagonistic relationship of NuA4 with non-homologous end joining (NHEJ) factors. We show that budding yeast Rad9, the 53BP1 ortholog, can inhibit NuA4 acetyltransferase activity when bound to chromatin in vitro. While we previously reported that NuA4 is recruited at DSBs during the S/G2 phase, we can also detect its recruitment in G1 when genes for Rad9 and NHEJ factors Yku80 and Nej1 are mutated. This is accompanied with the binding of single-strand DNA binding protein RPA and Rad52, indicating DNA end resection in G1 as well as recruitment of the HR machinery. This NuA4 recruitment to DSBs in G1 depends on Mre11-Rad50-Xrs2 (MRX) and Lcd1/Ddc2 and is linked to the hyper-resection phenotype of NHEJ mutants. It also implicates NuA4 in the resection-based single-strand annealing (SSA) repair pathway along Rad52. Interestingly, we identified two novel non-histone acetylation targets of NuA4, Nej1 and Yku80. Acetyl-mimicking mutant of Nej1 inhibits repair of DNA breaks by NHEJ, decreases its interaction with other core NHEJ factors such as Yku80 and Lif1 and favors end resection. Altogether, these results establish a strong reciprocal antagonistic regulatory function of NuA4 and NHEJ factors in repair pathway choice and suggests a role of NuA4 in alternative repair mechanisms in situations where some DNA-end resection can occur in G1. Author summary DNA double-strand breaks (DSBs) are one of the most harmful form of DNA damage. Cells employ two major repair pathways to resolve DSBs: Homologous Recombination (HR) and Non-Homologous End Joining (NHEJ). Here we wanted to dissect further the role played by the NuA4 (Nucleosome acetyltransferase of histone H4) complex in the repair of DSBs. Budding yeast NuA4 complex, like its mammalian homolog TIP60 complex, has been shown to favor repair by HR. Here, we show that indeed budding yeast NuA4 and components of the NHEJ repair pathway share an antagonistic relationship. Deletion of NHEJ components enables increased recruitment of NuA4 in the vicinity of DSBs, possible through two independent mechanisms, where NuA4 favors the end resection process which implicates it in repair by single-strand annealing (SSA), an alternate homology-based repair pathway. Additionally, we also present two NHEJ core components as new targets of NuA4 acetyltransferase activity and suggest that these acetylation events can disassemble the NHEJ repair complex from DSBs, favoring repair by HR. Our study demonstrates the importance of NuA4 in the modulation of DSB repair pathway choice. |
| Databáze: | OpenAIRE |
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