UBQLN4 is an ATM substrate that stabilizes the anti‐apoptotic proteins BCL2A1 and BCL2L10 in mesothelioma

ATM serine/threonine kinase (ATM; previously known as ataxia‐telangiectasia mutated) plays a critical role in maintaining genomic stability and regulates multiple downstream pathways, such as DNA repair, cell cycle arrest, and apoptosis. As a serine/threonine kinase, ATM has an array of downstream p...

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Autores principales:	Fang Liu, RunSang Pan, HongYu Ding, LiLing Gu, Yun Yang, ChuanYin Li, YongJie Xu, Ronggui Hu, Hui Chen, XiangYan Zhang, YingJie Nie
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	ATM BCL2A1 BCL2L10 mesothelioma UBQLN4 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/c30d625dab974349afe266e11ed47685
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spelling	oai:doaj.org-article:c30d625dab974349afe266e11ed476852021-12-02T10:31:07ZUBQLN4 is an ATM substrate that stabilizes the anti‐apoptotic proteins BCL2A1 and BCL2L10 in mesothelioma1878-02611574-789110.1002/1878-0261.13058https://doaj.org/article/c30d625dab974349afe266e11ed476852021-12-01T00:00:00Zhttps://doi.org/10.1002/1878-0261.13058https://doaj.org/toc/1574-7891https://doaj.org/toc/1878-0261ATM serine/threonine kinase (ATM; previously known as ataxia‐telangiectasia mutated) plays a critical role in maintaining genomic stability and regulates multiple downstream pathways, such as DNA repair, cell cycle arrest, and apoptosis. As a serine/threonine kinase, ATM has an array of downstream phosphorylation substrates, including checkpoint effector checkpoint kinase 2 (CHK2). ATM inhibits cell cycle progression by phosphorylating and activating CHK2, which plays an important role in the formation and development of tumors and participates in DNA repair responses after double‐stranded DNA breaks. In this study, we used a recently developed mammalian functional genetic screening system to explore a series of ATM substrates and their role in DNA damage to enhance our understanding of the DNA damage response. Ubiquilin 4 (UBQLN4), which belongs to the ubiquilin family characterized by its ubiquitin‐like (UBL) and ubiquitin‐associated (UBA) domains, was identified as a new substrate for ATM. UBQLN4 is involved in various intracellular processes, such as autophagosome maturation, p21 regulation, and motor axon morphogenesis. However, the biological function of UBQLN4 remains to be elucidated. In this study, we not only identified UBQLN4 as a substrate for ATM, but also found that UBQLN4 interacts with and stabilizes the anti‐apoptotic proteins Bcl‐2‐related protein A1 (BCL2A1) and Bcl‐2‐like protein 10 (BCL2L10) and prevents mesothelioma cell apoptosis in response to DNA damage. These findings expand our understanding of the role of UBQLN4 in mesothelioma and provide new insights into potential mesothelioma treatments targeting substrates for ATM.Fang LiuRunSang PanHongYu DingLiLing GuYun YangChuanYin LiYongJie XuRonggui HuHui ChenXiangYan ZhangYingJie NieWileyarticleATMBCL2A1BCL2L10mesotheliomaUBQLN4Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENMolecular Oncology, Vol 15, Iss 12, Pp 3738-3752 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ATM BCL2A1 BCL2L10 mesothelioma UBQLN4 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	ATM BCL2A1 BCL2L10 mesothelioma UBQLN4 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Fang Liu RunSang Pan HongYu Ding LiLing Gu Yun Yang ChuanYin Li YongJie Xu Ronggui Hu Hui Chen XiangYan Zhang YingJie Nie UBQLN4 is an ATM substrate that stabilizes the anti‐apoptotic proteins BCL2A1 and BCL2L10 in mesothelioma
description	ATM serine/threonine kinase (ATM; previously known as ataxia‐telangiectasia mutated) plays a critical role in maintaining genomic stability and regulates multiple downstream pathways, such as DNA repair, cell cycle arrest, and apoptosis. As a serine/threonine kinase, ATM has an array of downstream phosphorylation substrates, including checkpoint effector checkpoint kinase 2 (CHK2). ATM inhibits cell cycle progression by phosphorylating and activating CHK2, which plays an important role in the formation and development of tumors and participates in DNA repair responses after double‐stranded DNA breaks. In this study, we used a recently developed mammalian functional genetic screening system to explore a series of ATM substrates and their role in DNA damage to enhance our understanding of the DNA damage response. Ubiquilin 4 (UBQLN4), which belongs to the ubiquilin family characterized by its ubiquitin‐like (UBL) and ubiquitin‐associated (UBA) domains, was identified as a new substrate for ATM. UBQLN4 is involved in various intracellular processes, such as autophagosome maturation, p21 regulation, and motor axon morphogenesis. However, the biological function of UBQLN4 remains to be elucidated. In this study, we not only identified UBQLN4 as a substrate for ATM, but also found that UBQLN4 interacts with and stabilizes the anti‐apoptotic proteins Bcl‐2‐related protein A1 (BCL2A1) and Bcl‐2‐like protein 10 (BCL2L10) and prevents mesothelioma cell apoptosis in response to DNA damage. These findings expand our understanding of the role of UBQLN4 in mesothelioma and provide new insights into potential mesothelioma treatments targeting substrates for ATM.
format	article
author	Fang Liu RunSang Pan HongYu Ding LiLing Gu Yun Yang ChuanYin Li YongJie Xu Ronggui Hu Hui Chen XiangYan Zhang YingJie Nie
author_facet	Fang Liu RunSang Pan HongYu Ding LiLing Gu Yun Yang ChuanYin Li YongJie Xu Ronggui Hu Hui Chen XiangYan Zhang YingJie Nie
author_sort	Fang Liu
title	UBQLN4 is an ATM substrate that stabilizes the anti‐apoptotic proteins BCL2A1 and BCL2L10 in mesothelioma
title_short	UBQLN4 is an ATM substrate that stabilizes the anti‐apoptotic proteins BCL2A1 and BCL2L10 in mesothelioma
title_full	UBQLN4 is an ATM substrate that stabilizes the anti‐apoptotic proteins BCL2A1 and BCL2L10 in mesothelioma
title_fullStr	UBQLN4 is an ATM substrate that stabilizes the anti‐apoptotic proteins BCL2A1 and BCL2L10 in mesothelioma
title_full_unstemmed	UBQLN4 is an ATM substrate that stabilizes the anti‐apoptotic proteins BCL2A1 and BCL2L10 in mesothelioma
title_sort	ubqln4 is an atm substrate that stabilizes the anti‐apoptotic proteins bcl2a1 and bcl2l10 in mesothelioma
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/c30d625dab974349afe266e11ed47685
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UBQLN4 is an ATM substrate that stabilizes the anti‐apoptotic proteins BCL2A1 and BCL2L10 in mesothelioma

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