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ATM Activation by Oxidative Stress
The ataxia-telangiectasia mutated (ATM) protein kinase is activated by DNA double-strand breaks (DSBs) through the Mre11-Rad50-Nbs1 (MRN) DNA repair complex and orchestrates signaling cascades that initiate the DNA damage response. Cells lacking ATM are also hypersensitive to insults other than DSBs...
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| Published in: | Science (American Association for the Advancement of Science) 2010-10, Vol.330 (6003), p.517-521 |
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| cites | cdi_FETCH-LOGICAL-c538t-1ab6b8a5695ee9e7cd30cf1b37fadde5072eeb717a991119638a0bb21cf9cdbf3 |
| container_end_page | 521 |
| container_issue | 6003 |
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| container_title | Science (American Association for the Advancement of Science) |
| container_volume | 330 |
| creator | Guo, Zhi Kozlov, Sergei Lavin, Martin F Person, Maria D Paull, Tanya T |
| description | The ataxia-telangiectasia mutated (ATM) protein kinase is activated by DNA double-strand breaks (DSBs) through the Mre11-Rad50-Nbs1 (MRN) DNA repair complex and orchestrates signaling cascades that initiate the DNA damage response. Cells lacking ATM are also hypersensitive to insults other than DSBs, particularly oxidative stress. We show that oxidation of ATM directly induces ATM activation in the absence of DNA DSBs and the MRN complex. The oxidized form of ATM is a disulfide-cross-linked dimer, and mutation of a critical cysteine residue involved in disulfide bond formation specifically blocked activation through the oxidation pathway. Identification of this pathway explains observations of ATM activation under conditions of oxidative stress and shows that ATM is an important sensor of reactive oxygen species in human cells. |
| doi_str_mv | 10.1126/science.1192912 |
| format | article |
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Cells lacking ATM are also hypersensitive to insults other than DSBs, particularly oxidative stress. We show that oxidation of ATM directly induces ATM activation in the absence of DNA DSBs and the MRN complex. The oxidized form of ATM is a disulfide-cross-linked dimer, and mutation of a critical cysteine residue involved in disulfide bond formation specifically blocked activation through the oxidation pathway. Identification of this pathway explains observations of ATM activation under conditions of oxidative stress and shows that ATM is an important sensor of reactive oxygen species in human cells.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.1192912</identifier><identifier>PMID: 20966255</identifier><identifier>CODEN: SCIEAS</identifier><language>eng</language><publisher>Washington, DC: American Association for the Advancement of Science</publisher><subject>Acid Anhydride Hydrolases ; Activation ; Animals ; Ataxia telangiectasia ; Ataxia Telangiectasia - enzymology ; Ataxia Telangiectasia - genetics ; Ataxia Telangiectasia Mutated Proteins ; Automated teller machines ; Biological and medical sciences ; Cascades ; Cell Cycle Proteins - genetics ; Cell Cycle Proteins - metabolism ; Cell physiology ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; Cellular biology ; Cysteine ; Cysteine - metabolism ; Deoxyribonucleic acid ; Dimers ; Disulfides ; Disulfides - metabolism ; DNA ; DNA Breaks, Double-Stranded ; DNA damage ; DNA Repair ; DNA Repair Enzymes - genetics ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Enzyme Activation ; Fundamental and applied biological sciences. Psychology ; Genetic mutation ; Humans ; Hydrogen Peroxide ; Kinases ; Lymphocytes ; Molecular and cellular biology ; MRE11 Homologue Protein ; Mutation ; Nuclear Proteins - genetics ; Oxidation ; Oxidative Stress ; Pathways ; Phosphorylation ; Protein Serine-Threonine Kinases - genetics ; Protein Serine-Threonine Kinases - metabolism ; Stresses ; Tumor Suppressor Proteins - genetics ; Tumor Suppressor Proteins - metabolism</subject><ispartof>Science (American Association for the Advancement of Science), 2010-10, Vol.330 (6003), p.517-521</ispartof><rights>Copyright © 2010 American Association for the Advancement of Science</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2010, American Association for the Advancement of Science</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c538t-1ab6b8a5695ee9e7cd30cf1b37fadde5072eeb717a991119638a0bb21cf9cdbf3</citedby><cites>FETCH-LOGICAL-c538t-1ab6b8a5695ee9e7cd30cf1b37fadde5072eeb717a991119638a0bb21cf9cdbf3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/40931671$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/40931671$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>314,780,784,2884,2885,27924,27925,58238,58471</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23351284$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20966255$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Guo, Zhi</creatorcontrib><creatorcontrib>Kozlov, Sergei</creatorcontrib><creatorcontrib>Lavin, Martin F</creatorcontrib><creatorcontrib>Person, Maria D</creatorcontrib><creatorcontrib>Paull, Tanya T</creatorcontrib><title>ATM Activation by Oxidative Stress</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>The ataxia-telangiectasia mutated (ATM) protein kinase is activated by DNA double-strand breaks (DSBs) through the Mre11-Rad50-Nbs1 (MRN) DNA repair complex and orchestrates signaling cascades that initiate the DNA damage response. Cells lacking ATM are also hypersensitive to insults other than DSBs, particularly oxidative stress. We show that oxidation of ATM directly induces ATM activation in the absence of DNA DSBs and the MRN complex. The oxidized form of ATM is a disulfide-cross-linked dimer, and mutation of a critical cysteine residue involved in disulfide bond formation specifically blocked activation through the oxidation pathway. Identification of this pathway explains observations of ATM activation under conditions of oxidative stress and shows that ATM is an important sensor of reactive oxygen species in human cells.</description><subject>Acid Anhydride Hydrolases</subject><subject>Activation</subject><subject>Animals</subject><subject>Ataxia telangiectasia</subject><subject>Ataxia Telangiectasia - enzymology</subject><subject>Ataxia Telangiectasia - genetics</subject><subject>Ataxia Telangiectasia Mutated Proteins</subject><subject>Automated teller machines</subject><subject>Biological and medical sciences</subject><subject>Cascades</subject><subject>Cell Cycle Proteins - genetics</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>Cell physiology</subject><subject>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</subject><subject>Cellular biology</subject><subject>Cysteine</subject><subject>Cysteine - metabolism</subject><subject>Deoxyribonucleic acid</subject><subject>Dimers</subject><subject>Disulfides</subject><subject>Disulfides - metabolism</subject><subject>DNA</subject><subject>DNA Breaks, Double-Stranded</subject><subject>DNA damage</subject><subject>DNA Repair</subject><subject>DNA Repair Enzymes - genetics</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Enzyme Activation</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Genetic mutation</subject><subject>Humans</subject><subject>Hydrogen Peroxide</subject><subject>Kinases</subject><subject>Lymphocytes</subject><subject>Molecular and cellular biology</subject><subject>MRE11 Homologue Protein</subject><subject>Mutation</subject><subject>Nuclear Proteins - genetics</subject><subject>Oxidation</subject><subject>Oxidative Stress</subject><subject>Pathways</subject><subject>Phosphorylation</subject><subject>Protein Serine-Threonine Kinases - genetics</subject><subject>Protein Serine-Threonine Kinases - metabolism</subject><subject>Stresses</subject><subject>Tumor Suppressor Proteins - genetics</subject><subject>Tumor Suppressor Proteins - metabolism</subject><issn>0036-8075</issn><issn>1095-9203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><recordid>eNpdkM1LAzEQxYMotlbPntRSEE9rZ5Im2RyL-AWKB9tzSLJZ2dLu1mQr-t8b6VrB0_B4v3nMPEJOEa4RqRhHV_na-SQUVUj3SB9B8UxRYPukD8BEloPkPXIU4wIgeYodkh4FJQTlvE9G09nzcOra6sO0VVMP7dfw5bMqkvjww9c2-BiPyUFpltGfdHNA5ne3s5uH7Onl_vFm-pQ5zvI2Q2OFzQ0XinuvvHQFA1eiZbI0ReE5SOq9lSiNUpjuFSw3YC1FVypX2JINyNU2dx2a942PrV5V0fnl0tS-2USdM0SJmD4YkNE_ctFsQp2O05IrkFJJkaDxFnKhiTH4Uq9DtTLhSyPon_J0V57uyksb513sxq58seN_20rAZQeY6MyyDKZ2VfzjGONI80nizrbcIrZN2PkTUAyFxORfbP3SNNq8hZQxf6WADFAB5jln3yB2iZw</recordid><startdate>20101022</startdate><enddate>20101022</enddate><creator>Guo, Zhi</creator><creator>Kozlov, Sergei</creator><creator>Lavin, Martin F</creator><creator>Person, Maria D</creator><creator>Paull, Tanya T</creator><general>American Association for the Advancement of Science</general><general>The American Association for the Advancement of Science</general><scope>FBQ</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QF</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QQ</scope><scope>7QR</scope><scope>7SC</scope><scope>7SE</scope><scope>7SN</scope><scope>7SP</scope><scope>7SR</scope><scope>7SS</scope><scope>7T7</scope><scope>7TA</scope><scope>7TB</scope><scope>7TK</scope><scope>7TM</scope><scope>7U5</scope><scope>7U9</scope><scope>8BQ</scope><scope>8FD</scope><scope>C1K</scope><scope>F28</scope><scope>FR3</scope><scope>H8D</scope><scope>H8G</scope><scope>H94</scope><scope>JG9</scope><scope>JQ2</scope><scope>K9.</scope><scope>KR7</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20101022</creationdate><title>ATM Activation by Oxidative Stress</title><author>Guo, Zhi ; Kozlov, Sergei ; Lavin, Martin F ; Person, Maria D ; Paull, Tanya T</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c538t-1ab6b8a5695ee9e7cd30cf1b37fadde5072eeb717a991119638a0bb21cf9cdbf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Acid Anhydride Hydrolases</topic><topic>Activation</topic><topic>Animals</topic><topic>Ataxia telangiectasia</topic><topic>Ataxia Telangiectasia - enzymology</topic><topic>Ataxia Telangiectasia - genetics</topic><topic>Ataxia Telangiectasia Mutated Proteins</topic><topic>Automated teller machines</topic><topic>Biological and medical sciences</topic><topic>Cascades</topic><topic>Cell Cycle Proteins - genetics</topic><topic>Cell Cycle Proteins - metabolism</topic><topic>Cell physiology</topic><topic>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</topic><topic>Cellular biology</topic><topic>Cysteine</topic><topic>Cysteine - metabolism</topic><topic>Deoxyribonucleic acid</topic><topic>Dimers</topic><topic>Disulfides</topic><topic>Disulfides - metabolism</topic><topic>DNA</topic><topic>DNA Breaks, Double-Stranded</topic><topic>DNA damage</topic><topic>DNA Repair</topic><topic>DNA Repair Enzymes - genetics</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Enzyme Activation</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Genetic mutation</topic><topic>Humans</topic><topic>Hydrogen Peroxide</topic><topic>Kinases</topic><topic>Lymphocytes</topic><topic>Molecular and cellular biology</topic><topic>MRE11 Homologue Protein</topic><topic>Mutation</topic><topic>Nuclear Proteins - genetics</topic><topic>Oxidation</topic><topic>Oxidative Stress</topic><topic>Pathways</topic><topic>Phosphorylation</topic><topic>Protein Serine-Threonine Kinases - genetics</topic><topic>Protein Serine-Threonine Kinases - metabolism</topic><topic>Stresses</topic><topic>Tumor Suppressor Proteins - genetics</topic><topic>Tumor Suppressor Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Guo, Zhi</creatorcontrib><creatorcontrib>Kozlov, Sergei</creatorcontrib><creatorcontrib>Lavin, Martin F</creatorcontrib><creatorcontrib>Person, Maria D</creatorcontrib><creatorcontrib>Paull, Tanya T</creatorcontrib><collection>AGRIS</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Aluminium Industry Abstracts</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Ceramic Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Computer and Information Systems Abstracts</collection><collection>Corrosion Abstracts</collection><collection>Ecology Abstracts</collection><collection>Electronics & Communications Abstracts</collection><collection>Engineered Materials Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Materials Business File</collection><collection>Mechanical & Transportation Engineering Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Solid State and Superconductivity Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ANTE: Abstracts in New Technology & Engineering</collection><collection>Engineering Research Database</collection><collection>Aerospace Database</collection><collection>Copper Technical Reference Library</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Materials Research Database</collection><collection>ProQuest Computer Science Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Civil Engineering Abstracts</collection><collection>Advanced Technologies Database with Aerospace</collection><collection>Computer and Information Systems Abstracts Academic</collection><collection>Computer and Information Systems Abstracts Professional</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Science (American Association for the Advancement of Science)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Guo, Zhi</au><au>Kozlov, Sergei</au><au>Lavin, Martin F</au><au>Person, Maria D</au><au>Paull, Tanya T</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>ATM Activation by Oxidative Stress</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>2010-10-22</date><risdate>2010</risdate><volume>330</volume><issue>6003</issue><spage>517</spage><epage>521</epage><pages>517-521</pages><issn>0036-8075</issn><eissn>1095-9203</eissn><coden>SCIEAS</coden><abstract>The ataxia-telangiectasia mutated (ATM) protein kinase is activated by DNA double-strand breaks (DSBs) through the Mre11-Rad50-Nbs1 (MRN) DNA repair complex and orchestrates signaling cascades that initiate the DNA damage response. Cells lacking ATM are also hypersensitive to insults other than DSBs, particularly oxidative stress. We show that oxidation of ATM directly induces ATM activation in the absence of DNA DSBs and the MRN complex. The oxidized form of ATM is a disulfide-cross-linked dimer, and mutation of a critical cysteine residue involved in disulfide bond formation specifically blocked activation through the oxidation pathway. Identification of this pathway explains observations of ATM activation under conditions of oxidative stress and shows that ATM is an important sensor of reactive oxygen species in human cells.</abstract><cop>Washington, DC</cop><pub>American Association for the Advancement of Science</pub><pmid>20966255</pmid><doi>10.1126/science.1192912</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Science (American Association for the Advancement of Science), 2010-10, Vol.330 (6003), p.517-521 |
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| subjects | Acid Anhydride Hydrolases Activation Animals Ataxia telangiectasia Ataxia Telangiectasia - enzymology Ataxia Telangiectasia - genetics Ataxia Telangiectasia Mutated Proteins Automated teller machines Biological and medical sciences Cascades Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Cell physiology Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Cellular biology Cysteine Cysteine - metabolism Deoxyribonucleic acid Dimers Disulfides Disulfides - metabolism DNA DNA Breaks, Double-Stranded DNA damage DNA Repair DNA Repair Enzymes - genetics DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Enzyme Activation Fundamental and applied biological sciences. Psychology Genetic mutation Humans Hydrogen Peroxide Kinases Lymphocytes Molecular and cellular biology MRE11 Homologue Protein Mutation Nuclear Proteins - genetics Oxidation Oxidative Stress Pathways Phosphorylation Protein Serine-Threonine Kinases - genetics Protein Serine-Threonine Kinases - metabolism Stresses Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism |
| title | ATM Activation by Oxidative Stress |
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