Critical role of SMG7 in activation of the ATR-CHK1 axis in response to genotoxic stress

Abstract CHK1 is a crucial DNA damage checkpoint kinase and its activation, which requires ATR and RAD17, leads to inhibition of DNA replication and cell cycle progression. Recently, we reported that SMG7 stabilizes and activates p53 to induce G1 arrest upon DNA damage; here we show that SMG7 plays...

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Autores principales:	Kathleen Ho, Hongwei Luo, Wei Zhu, Yi Tang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/04c0408271c34af19719e98173db0624
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spelling	oai:doaj.org-article:04c0408271c34af19719e98173db06242021-12-02T14:37:39ZCritical role of SMG7 in activation of the ATR-CHK1 axis in response to genotoxic stress10.1038/s41598-021-86957-x2045-2322https://doaj.org/article/04c0408271c34af19719e98173db06242021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-86957-xhttps://doaj.org/toc/2045-2322Abstract CHK1 is a crucial DNA damage checkpoint kinase and its activation, which requires ATR and RAD17, leads to inhibition of DNA replication and cell cycle progression. Recently, we reported that SMG7 stabilizes and activates p53 to induce G1 arrest upon DNA damage; here we show that SMG7 plays a critical role in the activation of the ATR-CHK1 axis. Following genotoxic stress, SMG7-null cells exhibit deficient ATR signaling, indicated by the attenuated phosphorylation of CHK1 and RPA32, and importantly, unhindered DNA replication and fork progression. Through its 14-3-3 domain, SMG7 interacts directly with the Ser635-phosphorylated RAD17 and promotes chromatin retention of the 9-1-1 complex by the RAD17-RFC, an essential step to CHK1 activation. Furthermore, through maintenance of CHK1 activity, SMG7 controls G2-M transition and facilitates orderly cell cycle progression during recovery from replication stress. Taken together, our data reveals SMG7 as an indispensable signaling component in the ATR-CHK1 pathway during genotoxic stress response.Kathleen HoHongwei LuoWei ZhuYi TangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kathleen Ho Hongwei Luo Wei Zhu Yi Tang Critical role of SMG7 in activation of the ATR-CHK1 axis in response to genotoxic stress
description	Abstract CHK1 is a crucial DNA damage checkpoint kinase and its activation, which requires ATR and RAD17, leads to inhibition of DNA replication and cell cycle progression. Recently, we reported that SMG7 stabilizes and activates p53 to induce G1 arrest upon DNA damage; here we show that SMG7 plays a critical role in the activation of the ATR-CHK1 axis. Following genotoxic stress, SMG7-null cells exhibit deficient ATR signaling, indicated by the attenuated phosphorylation of CHK1 and RPA32, and importantly, unhindered DNA replication and fork progression. Through its 14-3-3 domain, SMG7 interacts directly with the Ser635-phosphorylated RAD17 and promotes chromatin retention of the 9-1-1 complex by the RAD17-RFC, an essential step to CHK1 activation. Furthermore, through maintenance of CHK1 activity, SMG7 controls G2-M transition and facilitates orderly cell cycle progression during recovery from replication stress. Taken together, our data reveals SMG7 as an indispensable signaling component in the ATR-CHK1 pathway during genotoxic stress response.
format	article
author	Kathleen Ho Hongwei Luo Wei Zhu Yi Tang
author_facet	Kathleen Ho Hongwei Luo Wei Zhu Yi Tang
author_sort	Kathleen Ho
title	Critical role of SMG7 in activation of the ATR-CHK1 axis in response to genotoxic stress
title_short	Critical role of SMG7 in activation of the ATR-CHK1 axis in response to genotoxic stress
title_full	Critical role of SMG7 in activation of the ATR-CHK1 axis in response to genotoxic stress
title_fullStr	Critical role of SMG7 in activation of the ATR-CHK1 axis in response to genotoxic stress
title_full_unstemmed	Critical role of SMG7 in activation of the ATR-CHK1 axis in response to genotoxic stress
title_sort	critical role of smg7 in activation of the atr-chk1 axis in response to genotoxic stress
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/04c0408271c34af19719e98173db0624
work_keys_str_mv	AT kathleenho criticalroleofsmg7inactivationoftheatrchk1axisinresponsetogenotoxicstress AT hongweiluo criticalroleofsmg7inactivationoftheatrchk1axisinresponsetogenotoxicstress AT weizhu criticalroleofsmg7inactivationoftheatrchk1axisinresponsetogenotoxicstress AT yitang criticalroleofsmg7inactivationoftheatrchk1axisinresponsetogenotoxicstress
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Critical role of SMG7 in activation of the ATR-CHK1 axis in response to genotoxic stress

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