A long noncoding RNA sensitizes genotoxic treatment by attenuating ATM activation and homologous recombination repair in cancers
Ataxia-telangiectasia mutated (ATM) is an apical kinase of the DNA damage response following DNA double-strand breaks (DSBs); however, the mechanisms of ATM activation are not completely understood. Long noncoding RNAs (lncRNAs) are a class of regulatory molecules whose significant roles in DNA dama...
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| description | Ataxia-telangiectasia mutated (ATM) is an apical kinase of the DNA damage response following DNA double-strand breaks (DSBs); however, the mechanisms of ATM activation are not completely understood. Long noncoding RNAs (lncRNAs) are a class of regulatory molecules whose significant roles in DNA damage response have started to emerge. However, how lncRNA regulates ATM activity remains unknown. Here, we identify an inhibitor of ATM activation, lncRNA HITT (HIF-1α inhibitor at translation level). Mechanistically, HITT directly interacts with ATM at the HEAT repeat domain, blocking MRE11-RAD50-NBS1 complex-dependent ATM recruitment, leading to restrained homologous recombination repair and enhanced chemosensitization. Following DSBs, HITT is elevated mainly by the activation of Early Growth Response 1 (EGR1), resulting in retarded and restricted ATM activation. A reverse association between HITT and ATM activity was also detected in human colon cancer tissues. Furthermore, HITTs sensitize DNA damaging agent-induced cell death both in vitro and in vivo. These findings connect lncRNA directly to ATM activity regulation and reveal potential roles for HITT in sensitizing cancers to genotoxic treatment. |
| doi_str_mv | 10.1371/journal.pbio.3000666 |
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Long noncoding RNAs (lncRNAs) are a class of regulatory molecules whose significant roles in DNA damage response have started to emerge. However, how lncRNA regulates ATM activity remains unknown. Here, we identify an inhibitor of ATM activation, lncRNA HITT (HIF-1α inhibitor at translation level). Mechanistically, HITT directly interacts with ATM at the HEAT repeat domain, blocking MRE11-RAD50-NBS1 complex-dependent ATM recruitment, leading to restrained homologous recombination repair and enhanced chemosensitization. Following DSBs, HITT is elevated mainly by the activation of Early Growth Response 1 (EGR1), resulting in retarded and restricted ATM activation. A reverse association between HITT and ATM activity was also detected in human colon cancer tissues. Furthermore, HITTs sensitize DNA damaging agent-induced cell death both in vitro and in vivo. These findings connect lncRNA directly to ATM activity regulation and reveal potential roles for HITT in sensitizing cancers to genotoxic treatment.</description><identifier>ISSN: 1545-7885</identifier><identifier>ISSN: 1544-9173</identifier><identifier>EISSN: 1545-7885</identifier><identifier>DOI: 10.1371/journal.pbio.3000666</identifier><identifier>PMID: 32203529</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acid Anhydride Hydrolases - metabolism ; Activation ; Animals ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Antisense RNA ; Apoptosis ; Apoptosis - drug effects ; Ataxia ; Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors ; Ataxia Telangiectasia Mutated Proteins - genetics ; Ataxia Telangiectasia Mutated Proteins - metabolism ; Binding Sites ; Biology and life sciences ; Biotechnology ; Cancer ; Cancer therapies ; Cell Cycle Proteins - genetics ; Cell Cycle Proteins - metabolism ; Cell death ; Chemosensitization ; Colon ; Colon cancer ; Colorectal cancer ; Damage ; Deoxyribonucleic acid ; DNA ; DNA Breaks, Double-Stranded - drug effects ; DNA Damage ; DNA repair ; DNA-Binding Proteins - metabolism ; Early Growth Response Protein 1 - genetics ; Early Growth Response Protein 1 - metabolism ; EGR-1 protein ; Genotoxicity ; HCT116 Cells ; HeLa Cells ; Homologous recombination ; Homologous recombination repair ; Homology ; Humans ; Hypoxia ; Inhibitors ; Ionizing radiation ; Kinases ; Life sciences ; Medicine and Health Sciences ; Mice ; Mice, Nude ; MRE11 Homologue Protein - metabolism ; MRE11 protein ; Mutation ; Neoplasms - drug therapy ; Neoplasms - genetics ; Neoplasms - metabolism ; Neoplasms - pathology ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; Phosphorylation ; Physiology ; Protein Binding ; Proteins ; Recombinational DNA Repair - genetics ; Recruitment ; Repair ; Research and analysis methods ; Ribonucleic acid ; RNA ; RNA, Long Noncoding - genetics ; RNA, Long Noncoding - metabolism ; Sensitizing ; Transcription, Genetic - drug effects ; Tumor necrosis factor-TNF</subject><ispartof>PLoS biology, 2020-03, Vol.18 (3), p.e3000666</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 Zhao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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drug effects</subject><subject>DNA Damage</subject><subject>DNA repair</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Early Growth Response Protein 1 - genetics</subject><subject>Early Growth Response Protein 1 - metabolism</subject><subject>EGR-1 protein</subject><subject>Genotoxicity</subject><subject>HCT116 Cells</subject><subject>HeLa Cells</subject><subject>Homologous recombination</subject><subject>Homologous recombination repair</subject><subject>Homology</subject><subject>Humans</subject><subject>Hypoxia</subject><subject>Inhibitors</subject><subject>Ionizing radiation</subject><subject>Kinases</subject><subject>Life sciences</subject><subject>Medicine and Health Sciences</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>MRE11 Homologue Protein - metabolism</subject><subject>MRE11 protein</subject><subject>Mutation</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - genetics</subject><subject>Neoplasms - metabolism</subject><subject>Neoplasms - pathology</subject><subject>Nuclear Proteins - genetics</subject><subject>Nuclear Proteins - metabolism</subject><subject>Phosphorylation</subject><subject>Physiology</subject><subject>Protein Binding</subject><subject>Proteins</subject><subject>Recombinational DNA Repair - genetics</subject><subject>Recruitment</subject><subject>Repair</subject><subject>Research and analysis methods</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA, Long Noncoding - genetics</subject><subject>RNA, Long Noncoding - metabolism</subject><subject>Sensitizing</subject><subject>Transcription, Genetic - drug effects</subject><subject>Tumor necrosis factor-TNF</subject><issn>1545-7885</issn><issn>1544-9173</issn><issn>1545-7885</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqVk0tv1DAUhSMEog_4BwgssYHFDH7kYW-QRhWPkUorlcLWunGc1KPEntpO1XbFT8fDpFUHdQHJIvb1d47jY90se0XwnLCKfFi50Vvo5-vauDnDGJdl-STbJ0VezCrOi6cPxnvZQQgrjCkVlD_P9hilmBVU7Ge_Fqh3tkPWWeUak0ZnJwsUtA0mmlsdUKeti-7aKBS9hjhoG1F9gyBGbUeIG8Xi_BsCFc1VmjqLwDbowg2ud50bA_JauaE2drvo9RqMR8YiBVZpH15kz1rog345fQ-zH58_nR99nR2fflkeLY5nqhRFnFHAUArBuKAM50AbwihLTytqQgvRMp7XtOU1lKylmuuC0xqnetPQghckZ4fZm63vundBTuEFSZnAFeGkwolYbonGwUquvRnA30gHRv4pON9J8NGoXkuAlhORK9ZQkhOoeNWmK6GkLjexVjR5fZx2G-tBNyql5qHfMd1dseZCdu5KVoRxRqpk8G4y8O5y1CHKwQSl-x6sTqmm_-a0LMoy5wl9-xf6-OkmqoN0AGNbl_ZVG1O5KIkgrMBcJGr-CJXeRg9GOatbk-o7gvc7gsREfR07GEOQy-9n_8Ge_Dt7-nOXzbes8i4Er9v7nAmWm165C0RuekVOvZJkrx_e0b3orjnYb_bBDmw</recordid><startdate>20200323</startdate><enddate>20200323</enddate><creator>Zhao, Kunming</creator><creator>Wang, Xingwen</creator><creator>Xue, Xuting</creator><creator>Li, Li</creator><creator>Hu, Ying</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>IOV</scope><scope>ISN</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>P64</scope><scope>PATMY</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><scope>CZG</scope><orcidid>https://orcid.org/0000-0003-2469-5604</orcidid></search><sort><creationdate>20200323</creationdate><title>A long noncoding RNA sensitizes genotoxic treatment by attenuating ATM activation and homologous recombination repair in cancers</title><author>Zhao, Kunming ; Wang, Xingwen ; Xue, Xuting ; Li, Li ; Hu, Ying</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c695t-2a0a6993892304a2d1323333f9b1259f384b2f8ba63f2e8e582b059fdd2585143</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Acid Anhydride Hydrolases - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><collection>PLoS Biology</collection><jtitle>PLoS biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhao, Kunming</au><au>Wang, Xingwen</au><au>Xue, Xuting</au><au>Li, Li</au><au>Hu, Ying</au><au>Paull, Tanya</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A long noncoding RNA sensitizes genotoxic treatment by attenuating ATM activation and homologous recombination repair in cancers</atitle><jtitle>PLoS biology</jtitle><addtitle>PLoS Biol</addtitle><date>2020-03-23</date><risdate>2020</risdate><volume>18</volume><issue>3</issue><spage>e3000666</spage><pages>e3000666-</pages><issn>1545-7885</issn><issn>1544-9173</issn><eissn>1545-7885</eissn><abstract>Ataxia-telangiectasia mutated (ATM) is an apical kinase of the DNA damage response following DNA double-strand breaks (DSBs); however, the mechanisms of ATM activation are not completely understood. Long noncoding RNAs (lncRNAs) are a class of regulatory molecules whose significant roles in DNA damage response have started to emerge. However, how lncRNA regulates ATM activity remains unknown. Here, we identify an inhibitor of ATM activation, lncRNA HITT (HIF-1α inhibitor at translation level). Mechanistically, HITT directly interacts with ATM at the HEAT repeat domain, blocking MRE11-RAD50-NBS1 complex-dependent ATM recruitment, leading to restrained homologous recombination repair and enhanced chemosensitization. Following DSBs, HITT is elevated mainly by the activation of Early Growth Response 1 (EGR1), resulting in retarded and restricted ATM activation. A reverse association between HITT and ATM activity was also detected in human colon cancer tissues. Furthermore, HITTs sensitize DNA damaging agent-induced cell death both in vitro and in vivo. These findings connect lncRNA directly to ATM activity regulation and reveal potential roles for HITT in sensitizing cancers to genotoxic treatment.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>32203529</pmid><doi>10.1371/journal.pbio.3000666</doi><orcidid>https://orcid.org/0000-0003-2469-5604</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Acid Anhydride Hydrolases - metabolism Activation Animals Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Antisense RNA Apoptosis Apoptosis - drug effects Ataxia Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors Ataxia Telangiectasia Mutated Proteins - genetics Ataxia Telangiectasia Mutated Proteins - metabolism Binding Sites Biology and life sciences Biotechnology Cancer Cancer therapies Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Cell death Chemosensitization Colon Colon cancer Colorectal cancer Damage Deoxyribonucleic acid DNA DNA Breaks, Double-Stranded - drug effects DNA Damage DNA repair DNA-Binding Proteins - metabolism Early Growth Response Protein 1 - genetics Early Growth Response Protein 1 - metabolism EGR-1 protein Genotoxicity HCT116 Cells HeLa Cells Homologous recombination Homologous recombination repair Homology Humans Hypoxia Inhibitors Ionizing radiation Kinases Life sciences Medicine and Health Sciences Mice Mice, Nude MRE11 Homologue Protein - metabolism MRE11 protein Mutation Neoplasms - drug therapy Neoplasms - genetics Neoplasms - metabolism Neoplasms - pathology Nuclear Proteins - genetics Nuclear Proteins - metabolism Phosphorylation Physiology Protein Binding Proteins Recombinational DNA Repair - genetics Recruitment Repair Research and analysis methods Ribonucleic acid RNA RNA, Long Noncoding - genetics RNA, Long Noncoding - metabolism Sensitizing Transcription, Genetic - drug effects Tumor necrosis factor-TNF |
| title | A long noncoding RNA sensitizes genotoxic treatment by attenuating ATM activation and homologous recombination repair in cancers |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-20T12%3A32%3A08IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20long%20noncoding%20RNA%20sensitizes%20genotoxic%20treatment%20by%20attenuating%20ATM%20activation%20and%20homologous%20recombination%20repair%20in%20cancers&rft.jtitle=PLoS%20biology&rft.au=Zhao,%20Kunming&rft.date=2020-03-23&rft.volume=18&rft.issue=3&rft.spage=e3000666&rft.pages=e3000666-&rft.issn=1545-7885&rft.eissn=1545-7885&rft_id=info:doi/10.1371/journal.pbio.3000666&rft_dat=%3Cgale_plos_%3EA619135089%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2390718170&rft_id=info:pmid/32203529&rft_galeid=A619135089&rft_doaj_id=oai_doaj_org_article_aaf8194c3d2141a787f37121b6035272&rfr_iscdi=true |