A novel role for ATR/Rad3 in G1 phase

Abstract Checkpoint kinases are important in cellular surveillance pathways that help cells to cope with DNA damage and protect their genomes. In cycling cells, DNA replication is one of the most sensitive processes and therefore all organisms carefully regulate replication initiation and progressio...

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Autores principales:	Cathrine A. Bøe, Tine W. Håland, Erik Boye, Randi G. Syljuåsen, Beáta Grallert
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9e8ac8dcb38b4280adc4d709977a6bdc
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spelling	oai:doaj.org-article:9e8ac8dcb38b4280adc4d709977a6bdc2021-12-02T11:40:26ZA novel role for ATR/Rad3 in G1 phase10.1038/s41598-018-25238-62045-2322https://doaj.org/article/9e8ac8dcb38b4280adc4d709977a6bdc2018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25238-6https://doaj.org/toc/2045-2322Abstract Checkpoint kinases are important in cellular surveillance pathways that help cells to cope with DNA damage and protect their genomes. In cycling cells, DNA replication is one of the most sensitive processes and therefore all organisms carefully regulate replication initiation and progression. The checkpoint kinase ATR plays important roles both in response to DNA damage and replication stress, and ATR inhibitors are currently in clinical trials for cancer treatment. Therefore, it is important to understand the roles of ATR in detail. Here we show that the fission yeast homologue Rad3 and the human ATR regulate events also in G1 phase in an unperturbed cell cycle. Rad3Δ mutants or human cells exposed to ATR inhibitor in G1 enter S phase prematurely, which results in increased DNA damage. Furthermore, ATR inhibition in a single G1 reduces clonogenic survival, demonstrating that long-term effects of ATR inhibition during G1 are deleterious for the cell. Interestingly, ATR inhibition through G1 and S phase reduces survival in an additive manner, strongly arguing that different functions of ATR are targeted in the different cell-cycle phases. We propose that potential effects of ATR inhibitors in G1 should be considered when designing future treatment protocols with such inhibitors.Cathrine A. BøeTine W. HålandErik BoyeRandi G. SyljuåsenBeáta GrallertNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-12 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Cathrine A. Bøe Tine W. Håland Erik Boye Randi G. Syljuåsen Beáta Grallert A novel role for ATR/Rad3 in G1 phase
description	Abstract Checkpoint kinases are important in cellular surveillance pathways that help cells to cope with DNA damage and protect their genomes. In cycling cells, DNA replication is one of the most sensitive processes and therefore all organisms carefully regulate replication initiation and progression. The checkpoint kinase ATR plays important roles both in response to DNA damage and replication stress, and ATR inhibitors are currently in clinical trials for cancer treatment. Therefore, it is important to understand the roles of ATR in detail. Here we show that the fission yeast homologue Rad3 and the human ATR regulate events also in G1 phase in an unperturbed cell cycle. Rad3Δ mutants or human cells exposed to ATR inhibitor in G1 enter S phase prematurely, which results in increased DNA damage. Furthermore, ATR inhibition in a single G1 reduces clonogenic survival, demonstrating that long-term effects of ATR inhibition during G1 are deleterious for the cell. Interestingly, ATR inhibition through G1 and S phase reduces survival in an additive manner, strongly arguing that different functions of ATR are targeted in the different cell-cycle phases. We propose that potential effects of ATR inhibitors in G1 should be considered when designing future treatment protocols with such inhibitors.
format	article
author	Cathrine A. Bøe Tine W. Håland Erik Boye Randi G. Syljuåsen Beáta Grallert
author_facet	Cathrine A. Bøe Tine W. Håland Erik Boye Randi G. Syljuåsen Beáta Grallert
author_sort	Cathrine A. Bøe
title	A novel role for ATR/Rad3 in G1 phase
title_short	A novel role for ATR/Rad3 in G1 phase
title_full	A novel role for ATR/Rad3 in G1 phase
title_fullStr	A novel role for ATR/Rad3 in G1 phase
title_full_unstemmed	A novel role for ATR/Rad3 in G1 phase
title_sort	novel role for atr/rad3 in g1 phase
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/9e8ac8dcb38b4280adc4d709977a6bdc
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A novel role for ATR/Rad3 in G1 phase

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