ATM Kinase Dead: From Ataxia Telangiectasia Syndrome to Cancer

ATM is one of the principal players of the DNA damage response. This protein exerts its role in DNA repair during cell cycle replication, oxidative stress, and DNA damage from endogenous events or exogenous agents. When is activated, ATM phosphorylates multiple substrates that participate in DNA rep...

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Autores principales:	Sabrina Putti, Alessandro Giovinazzo, Matilde Merolle, Maria Laura Falchetti, Manuela Pellegrini
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	<i>ATM</i> A-T patients ATM kinase activity ATM-KD and cancer Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/dc02e8f0757c44eba5e0b81ba3854808
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spelling	oai:doaj.org-article:dc02e8f0757c44eba5e0b81ba38548082021-11-11T15:33:44ZATM Kinase Dead: From Ataxia Telangiectasia Syndrome to Cancer10.3390/cancers132154982072-6694https://doaj.org/article/dc02e8f0757c44eba5e0b81ba38548082021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5498https://doaj.org/toc/2072-6694ATM is one of the principal players of the DNA damage response. This protein exerts its role in DNA repair during cell cycle replication, oxidative stress, and DNA damage from endogenous events or exogenous agents. When is activated, ATM phosphorylates multiple substrates that participate in DNA repair, through its phosphoinositide 3-kinase like domain at the 3′end of the protein. The absence of ATM is the cause of a rare autosomal recessive disorder called Ataxia Telangiectasia characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility, and radiation sensitivity. There is a correlation between the severity of the phenotype and the mutations, depending on the residual activity of the protein. The analysis of patient mutations and mouse models revealed that the presence of inactive ATM, named ATM kinase-dead, is more cancer prone and lethal than its absence. <i>ATM</i> mutations fall into the whole gene sequence, and it is very difficult to predict the resulting effects, except for some frequent mutations. In this regard, is necessary to characterize the mutated protein to assess if it is stable and maintains some residual kinase activity. Moreover, the whole-genome sequencing of cancer patients with somatic or germline mutations has highlighted a high percentage of <i>ATM</i> mutations in the phosphoinositide 3-kinase domain, mostly in cancer cells resistant to classical therapy. The relevant differences between the complete absence of ATM and the presence of the inactive form in in vitro and in vivo models need to be explored in more detail to predict cancer predisposition of A-T patients and to discover new therapies for ATM-associated cancer cells. In this review, we summarize the multiple discoveries from humans and mouse models on ATM mutations, focusing into the inactive versus null ATM.Sabrina PuttiAlessandro GiovinazzoMatilde MerolleMaria Laura FalchettiManuela PellegriniMDPI AGarticle<i>ATM</i>A-T patientsATM kinase activityATM-KD and cancerNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5498, p 5498 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	<i>ATM</i> A-T patients ATM kinase activity ATM-KD and cancer Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	<i>ATM</i> A-T patients ATM kinase activity ATM-KD and cancer Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Sabrina Putti Alessandro Giovinazzo Matilde Merolle Maria Laura Falchetti Manuela Pellegrini ATM Kinase Dead: From Ataxia Telangiectasia Syndrome to Cancer
description	ATM is one of the principal players of the DNA damage response. This protein exerts its role in DNA repair during cell cycle replication, oxidative stress, and DNA damage from endogenous events or exogenous agents. When is activated, ATM phosphorylates multiple substrates that participate in DNA repair, through its phosphoinositide 3-kinase like domain at the 3′end of the protein. The absence of ATM is the cause of a rare autosomal recessive disorder called Ataxia Telangiectasia characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility, and radiation sensitivity. There is a correlation between the severity of the phenotype and the mutations, depending on the residual activity of the protein. The analysis of patient mutations and mouse models revealed that the presence of inactive ATM, named ATM kinase-dead, is more cancer prone and lethal than its absence. <i>ATM</i> mutations fall into the whole gene sequence, and it is very difficult to predict the resulting effects, except for some frequent mutations. In this regard, is necessary to characterize the mutated protein to assess if it is stable and maintains some residual kinase activity. Moreover, the whole-genome sequencing of cancer patients with somatic or germline mutations has highlighted a high percentage of <i>ATM</i> mutations in the phosphoinositide 3-kinase domain, mostly in cancer cells resistant to classical therapy. The relevant differences between the complete absence of ATM and the presence of the inactive form in in vitro and in vivo models need to be explored in more detail to predict cancer predisposition of A-T patients and to discover new therapies for ATM-associated cancer cells. In this review, we summarize the multiple discoveries from humans and mouse models on ATM mutations, focusing into the inactive versus null ATM.
format	article
author	Sabrina Putti Alessandro Giovinazzo Matilde Merolle Maria Laura Falchetti Manuela Pellegrini
author_facet	Sabrina Putti Alessandro Giovinazzo Matilde Merolle Maria Laura Falchetti Manuela Pellegrini
author_sort	Sabrina Putti
title	ATM Kinase Dead: From Ataxia Telangiectasia Syndrome to Cancer
title_short	ATM Kinase Dead: From Ataxia Telangiectasia Syndrome to Cancer
title_full	ATM Kinase Dead: From Ataxia Telangiectasia Syndrome to Cancer
title_fullStr	ATM Kinase Dead: From Ataxia Telangiectasia Syndrome to Cancer
title_full_unstemmed	ATM Kinase Dead: From Ataxia Telangiectasia Syndrome to Cancer
title_sort	atm kinase dead: from ataxia telangiectasia syndrome to cancer
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/dc02e8f0757c44eba5e0b81ba3854808
work_keys_str_mv	AT sabrinaputti atmkinasedeadfromataxiatelangiectasiasyndrometocancer AT alessandrogiovinazzo atmkinasedeadfromataxiatelangiectasiasyndrometocancer AT matildemerolle atmkinasedeadfromataxiatelangiectasiasyndrometocancer AT marialaurafalchetti atmkinasedeadfromataxiatelangiectasiasyndrometocancer AT manuelapellegrini atmkinasedeadfromataxiatelangiectasiasyndrometocancer
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ATM Kinase Dead: From Ataxia Telangiectasia Syndrome to Cancer

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