Antagonistic relationship of NuA4 with the non-homologous end-joining machinery at DNA damage sites.

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 Nu...

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Autores principales:	Salar Ahmad, Valérie Côté, Xue Cheng, Gaëlle Bourriquen, Vasileia Sapountzi, Mohammed Altaf, Jacques Côté
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/91831aa9281044388e22d5c6c7481cc1
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spelling	oai:doaj.org-article:91831aa9281044388e22d5c6c7481cc12021-12-02T20:03:19ZAntagonistic relationship of NuA4 with the non-homologous end-joining machinery at DNA damage sites.1553-73901553-740410.1371/journal.pgen.1009816https://doaj.org/article/91831aa9281044388e22d5c6c7481cc12021-09-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009816https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404The 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.Salar AhmadValérie CôtéXue ChengGaëlle BourriquenVasileia SapountziMohammed AltafJacques CôtéPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 9, p e1009816 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Salar Ahmad Valérie Côté Xue Cheng Gaëlle Bourriquen Vasileia Sapountzi Mohammed Altaf Jacques Côté Antagonistic relationship of NuA4 with the non-homologous end-joining machinery at DNA damage sites.
description	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.
format	article
author	Salar Ahmad Valérie Côté Xue Cheng Gaëlle Bourriquen Vasileia Sapountzi Mohammed Altaf Jacques Côté
author_facet	Salar Ahmad Valérie Côté Xue Cheng Gaëlle Bourriquen Vasileia Sapountzi Mohammed Altaf Jacques Côté
author_sort	Salar Ahmad
title	Antagonistic relationship of NuA4 with the non-homologous end-joining machinery at DNA damage sites.
title_short	Antagonistic relationship of NuA4 with the non-homologous end-joining machinery at DNA damage sites.
title_full	Antagonistic relationship of NuA4 with the non-homologous end-joining machinery at DNA damage sites.
title_fullStr	Antagonistic relationship of NuA4 with the non-homologous end-joining machinery at DNA damage sites.
title_full_unstemmed	Antagonistic relationship of NuA4 with the non-homologous end-joining machinery at DNA damage sites.
title_sort	antagonistic relationship of nua4 with the non-homologous end-joining machinery at dna damage sites.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/91831aa9281044388e22d5c6c7481cc1
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Antagonistic relationship of NuA4 with the non-homologous end-joining machinery at DNA damage sites.

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