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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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. ATM 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 ATM 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. |
doi_str_mv | 10.3390/cancers13215498 |
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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. ATM 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 ATM 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.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers13215498</identifier><identifier>PMID: 34771661</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>Amino acids ; Animal models ; Ataxia ; Ataxia telangiectasia ; Ataxia telangiectasia mutated protein ; Cancer ; Cell cycle ; Cerebellum ; Deoxyribonucleic acid ; DNA ; DNA biosynthesis ; DNA damage ; DNA repair ; Genomes ; Genotype & phenotype ; Hereditary diseases ; Immunodeficiency ; Kinases ; Medical prognosis ; Metabolism ; Mutation ; Neurodegeneration ; Oxidative stress ; Patients ; Phenotypes ; Phosphorylation ; Physiology ; Proteins ; Review ; Tumors ; Whole genome sequencing</subject><ispartof>Cancers, 2021-11, Vol.13 (21), p.5498</ispartof><rights>2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 by the authors. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c464t-ef03ee9e2764268167d32f15a76b7a741964dca8031c3534435d5a13dce27a783</citedby><cites>FETCH-LOGICAL-c464t-ef03ee9e2764268167d32f15a76b7a741964dca8031c3534435d5a13dce27a783</cites><orcidid>0000-0001-6387-5187 ; 0000-0003-4420-6257 ; 0000-0002-8755-0042 ; 0000-0003-3335-043X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583659/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583659/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids></links><search><creatorcontrib>Putti, Sabrina</creatorcontrib><creatorcontrib>Giovinazzo, Alessandro</creatorcontrib><creatorcontrib>Merolle, Matilde</creatorcontrib><creatorcontrib>Falchetti, Maria Laura</creatorcontrib><creatorcontrib>Pellegrini, Manuela</creatorcontrib><title>ATM Kinase Dead: From Ataxia Telangiectasia Syndrome to Cancer</title><title>Cancers</title><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. ATM 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 ATM 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.</description><subject>Amino acids</subject><subject>Animal models</subject><subject>Ataxia</subject><subject>Ataxia telangiectasia</subject><subject>Ataxia telangiectasia mutated protein</subject><subject>Cancer</subject><subject>Cell cycle</subject><subject>Cerebellum</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA biosynthesis</subject><subject>DNA damage</subject><subject>DNA repair</subject><subject>Genomes</subject><subject>Genotype & phenotype</subject><subject>Hereditary diseases</subject><subject>Immunodeficiency</subject><subject>Kinases</subject><subject>Medical prognosis</subject><subject>Metabolism</subject><subject>Mutation</subject><subject>Neurodegeneration</subject><subject>Oxidative stress</subject><subject>Patients</subject><subject>Phenotypes</subject><subject>Phosphorylation</subject><subject>Physiology</subject><subject>Proteins</subject><subject>Review</subject><subject>Tumors</subject><subject>Whole genome sequencing</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkU1PwzAMhiMEYmjszLUSFy5lSZ2PlsOkaTBADHFgnKMsTUenthlJi9i_J2MTguXi2H782pYRuiD4GiDDQ60abZwnkBBGs_QInSVYJDHnGT3-8--hgfcrHB4AEVycoh5QIQjn5AyNxvPn6KlslDfRrVH5TTR1to7GrfoqVTQ3lWqWpdGt8sF93TR5yJqotdHkp_k5OilU5c1gb_vobXo3nzzEs5f7x8l4FmvKaRubAoMxmUkEpwlPCRc5JAVhSvCFUIKSjNNcqxQD0cCAUmA5UwRyHUqUSKGPRjvddbeoTQg3rVOVXLuyVm4jrSrl_0xTvsul_ZQpS4GzLAhc7QWc_eiMb2Vdem2qsJ-xnZcJywTNGBcioJcH6Mp2rgnrbSmOCeGAAzXcUdpZ750pfochWG7PIw_OA98mD4CL</recordid><startdate>20211101</startdate><enddate>20211101</enddate><creator>Putti, Sabrina</creator><creator>Giovinazzo, Alessandro</creator><creator>Merolle, Matilde</creator><creator>Falchetti, Maria Laura</creator><creator>Pellegrini, Manuela</creator><general>MDPI AG</general><general>MDPI</general><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7TO</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-6387-5187</orcidid><orcidid>https://orcid.org/0000-0003-4420-6257</orcidid><orcidid>https://orcid.org/0000-0002-8755-0042</orcidid><orcidid>https://orcid.org/0000-0003-3335-043X</orcidid></search><sort><creationdate>20211101</creationdate><title>ATM Kinase Dead: From Ataxia Telangiectasia Syndrome to Cancer</title><author>Putti, Sabrina ; 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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. ATM 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 ATM 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.</abstract><cop>Basel</cop><pub>MDPI AG</pub><pmid>34771661</pmid><doi>10.3390/cancers13215498</doi><orcidid>https://orcid.org/0000-0001-6387-5187</orcidid><orcidid>https://orcid.org/0000-0003-4420-6257</orcidid><orcidid>https://orcid.org/0000-0002-8755-0042</orcidid><orcidid>https://orcid.org/0000-0003-3335-043X</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Amino acids Animal models Ataxia Ataxia telangiectasia Ataxia telangiectasia mutated protein Cancer Cell cycle Cerebellum Deoxyribonucleic acid DNA DNA biosynthesis DNA damage DNA repair Genomes Genotype & phenotype Hereditary diseases Immunodeficiency Kinases Medical prognosis Metabolism Mutation Neurodegeneration Oxidative stress Patients Phenotypes Phosphorylation Physiology Proteins Review Tumors Whole genome sequencing |
title | ATM Kinase Dead: From Ataxia Telangiectasia Syndrome to Cancer |
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