Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice
Non‐homologous end joining (NHEJ) is the principal repair mechanism used by mammalian cells to cope with double‐strand breaks (DSBs) that continually occur in the genome. One of the key components of the mammalian NHEJ machinery is the DNA‐PK complex, formed by the Ku86/70 heterodimer and the DNA‐PK...
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| Veröffentlicht in: | EMBO reports 2004-05, Vol.5 (5), p.503-509 |
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| creator | Espejel, Silvia Martín, Marta Klatt, Peter Martín-Caballero, Juan Flores, Juana M Blasco, María A |
| description | Non‐homologous end joining (NHEJ) is the principal repair mechanism used by mammalian cells to cope with double‐strand breaks (DSBs) that continually occur in the genome. One of the key components of the mammalian NHEJ machinery is the DNA‐PK complex, formed by the Ku86/70 heterodimer and the DNA‐PK catalytic subunit (DNA‐PKcs). Here, we report on the detailed life‐long follow‐up of DNA‐PKcs‐defective mice. Apart from defining a role of DNA‐PKcs in telomere length maintenance in the context of the ageing organism, we observed that DNA‐PKcs‐defective mice had a shorter life span and showed an earlier onset of ageing‐related pathologies than the corresponding wild‐type littermates. In addition, DNA‐PKcs ablation was associated with a markedly higher incidence of T lymphomas and infections. In conclusion, these data link the dual role of DNA‐PKcs in DNA repair and telomere length maintenance to organismal ageing and cancer. |
| doi_str_mv | 10.1038/sj.embor.7400127 |
| format | Article |
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One of the key components of the mammalian NHEJ machinery is the DNA‐PK complex, formed by the Ku86/70 heterodimer and the DNA‐PK catalytic subunit (DNA‐PKcs). Here, we report on the detailed life‐long follow‐up of DNA‐PKcs‐defective mice. Apart from defining a role of DNA‐PKcs in telomere length maintenance in the context of the ageing organism, we observed that DNA‐PKcs‐defective mice had a shorter life span and showed an earlier onset of ageing‐related pathologies than the corresponding wild‐type littermates. In addition, DNA‐PKcs ablation was associated with a markedly higher incidence of T lymphomas and infections. In conclusion, these data link the dual role of DNA‐PKcs in DNA repair and telomere length maintenance to organismal ageing and cancer.</description><identifier>ISSN: 1469-221X</identifier><identifier>EISSN: 1469-3178</identifier><identifier>EISSN: 1469-221X</identifier><identifier>DOI: 10.1038/sj.embor.7400127</identifier><identifier>PMID: 15105825</identifier><identifier>CODEN: ERMEAX</identifier><language>eng</language><publisher>Chichester, UK: John Wiley & Sons, Ltd</publisher><subject>ageing ; Aging - genetics ; Aging - physiology ; Animals ; Body Weight ; cancer ; Cell Cycle ; Chromosomes - metabolism ; Chromosomes - ultrastructure ; Deoxyribonucleic acid ; DNA ; DNA Damage ; DNA Repair ; DNA-Activated Protein Kinase ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; DNA-PKcs ; Female ; Life Expectancy ; Life span ; Lymphoma ; Lymphoma - genetics ; Lymphoma - metabolism ; Male ; Mammals ; Meiosis ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Nuclear Proteins ; Protein-Serine-Threonine Kinases - genetics ; Protein-Serine-Threonine Kinases - metabolism ; Scientific Report ; Spine - abnormalities ; Telomere - metabolism ; telomeres ; Testis - cytology</subject><ispartof>EMBO reports, 2004-05, Vol.5 (5), p.503-509</ispartof><rights>European Molecular Biology Organization 2004</rights><rights>Copyright © 2004 European Molecular Biology Organization</rights><rights>Copyright Nature Publishing Group May 2004</rights><rights>Copyright © 2004, European Molecular Biology Organization 2004</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c6027-ca8478c2e4de3e9585760179cdd21f7424584260b92f4b8221c6f674c6d2d7123</citedby><cites>FETCH-LOGICAL-c6027-ca8478c2e4de3e9585760179cdd21f7424584260b92f4b8221c6f674c6d2d7123</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1299048/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1299048/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,1416,1432,27915,27916,45565,45566,46400,46824,53782,53784</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15105825$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Espejel, Silvia</creatorcontrib><creatorcontrib>Martín, Marta</creatorcontrib><creatorcontrib>Klatt, Peter</creatorcontrib><creatorcontrib>Martín-Caballero, Juan</creatorcontrib><creatorcontrib>Flores, Juana M</creatorcontrib><creatorcontrib>Blasco, María A</creatorcontrib><title>Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice</title><title>EMBO reports</title><addtitle>EMBO Rep</addtitle><addtitle>EMBO Rep</addtitle><description>Non‐homologous end joining (NHEJ) is the principal repair mechanism used by mammalian cells to cope with double‐strand breaks (DSBs) that continually occur in the genome. One of the key components of the mammalian NHEJ machinery is the DNA‐PK complex, formed by the Ku86/70 heterodimer and the DNA‐PK catalytic subunit (DNA‐PKcs). Here, we report on the detailed life‐long follow‐up of DNA‐PKcs‐defective mice. Apart from defining a role of DNA‐PKcs in telomere length maintenance in the context of the ageing organism, we observed that DNA‐PKcs‐defective mice had a shorter life span and showed an earlier onset of ageing‐related pathologies than the corresponding wild‐type littermates. In addition, DNA‐PKcs ablation was associated with a markedly higher incidence of T lymphomas and infections. In conclusion, these data link the dual role of DNA‐PKcs in DNA repair and telomere length maintenance to organismal ageing and cancer.</description><subject>ageing</subject><subject>Aging - genetics</subject><subject>Aging - physiology</subject><subject>Animals</subject><subject>Body Weight</subject><subject>cancer</subject><subject>Cell Cycle</subject><subject>Chromosomes - metabolism</subject><subject>Chromosomes - ultrastructure</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA Damage</subject><subject>DNA Repair</subject><subject>DNA-Activated Protein Kinase</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>DNA-PKcs</subject><subject>Female</subject><subject>Life Expectancy</subject><subject>Life span</subject><subject>Lymphoma</subject><subject>Lymphoma - genetics</subject><subject>Lymphoma - metabolism</subject><subject>Male</subject><subject>Mammals</subject><subject>Meiosis</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Nuclear Proteins</subject><subject>Protein-Serine-Threonine Kinases - genetics</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Scientific Report</subject><subject>Spine - abnormalities</subject><subject>Telomere - metabolism</subject><subject>telomeres</subject><subject>Testis - cytology</subject><issn>1469-221X</issn><issn>1469-3178</issn><issn>1469-221X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqFUU1v0zAYjhCIjcGdCyjiwGkptmPH9gVpdGMg1vE1VMTFcp03rUsSd3YC9N9jSNQCB3ay9T4f78eTJA8xmmCUi2dhPYFm4fyEU4Qw4beSQ0wLmeWYi9vjnxD8-SC5F8IaIcQkF3eTA8wwYoKww2T-ceV8Bz7toHYNeAjHqTYGavC6gzLVS7DtMtVtmdrWeNAhFutts1m5RsdSenp5kr17Y0JWQmWNhbZLG2vgfnKn0nWAB-N7lHx6eXY1fZVdvD1_PT25yEyBCM-MFpQLQ4CWkINkgvECYS5NWRJccUooE5QUaCFJRRci7mKKquDUFCUpOSb5UfJ88N30iwZKE_t7XauNt432W-W0VX8jrV2ppfumMJESURENno4G3l33EDrV2BD3r3ULrg-KYymJFOhGYuQVPCcsEp_8Q1y73rfxCoogwQiiuYwkNJCMdyF4qHYjY6R-ZavCWv3OVo3ZRsnjP1fdC8YwI0EOhO-2hu2Nhups9uLD3hwP2hBl7RL8fuj_DPRo0LS66z3sGu7xbMBt6ODHDtb-q4qX4kzNL8_VLJ_P3p9Ov6ir_Cf7C9xs</recordid><startdate>200405</startdate><enddate>200405</enddate><creator>Espejel, Silvia</creator><creator>Martín, Marta</creator><creator>Klatt, Peter</creator><creator>Martín-Caballero, Juan</creator><creator>Flores, Juana M</creator><creator>Blasco, María A</creator><general>John Wiley & Sons, Ltd</general><general>Nature Publishing Group UK</general><general>Blackwell Publishing Ltd</general><scope>BSCLL</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>3V.</scope><scope>7QL</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</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>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7N</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>200405</creationdate><title>Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice</title><author>Espejel, Silvia ; Martín, Marta ; Klatt, Peter ; Martín-Caballero, Juan ; Flores, Juana M ; Blasco, María A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c6027-ca8478c2e4de3e9585760179cdd21f7424584260b92f4b8221c6f674c6d2d7123</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>ageing</topic><topic>Aging - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>EMBO reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Espejel, Silvia</au><au>Martín, Marta</au><au>Klatt, Peter</au><au>Martín-Caballero, Juan</au><au>Flores, Juana M</au><au>Blasco, María A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice</atitle><jtitle>EMBO reports</jtitle><stitle>EMBO Rep</stitle><addtitle>EMBO Rep</addtitle><date>2004-05</date><risdate>2004</risdate><volume>5</volume><issue>5</issue><spage>503</spage><epage>509</epage><pages>503-509</pages><issn>1469-221X</issn><eissn>1469-3178</eissn><eissn>1469-221X</eissn><coden>ERMEAX</coden><abstract>Non‐homologous end joining (NHEJ) is the principal repair mechanism used by mammalian cells to cope with double‐strand breaks (DSBs) that continually occur in the genome. One of the key components of the mammalian NHEJ machinery is the DNA‐PK complex, formed by the Ku86/70 heterodimer and the DNA‐PK catalytic subunit (DNA‐PKcs). Here, we report on the detailed life‐long follow‐up of DNA‐PKcs‐defective mice. Apart from defining a role of DNA‐PKcs in telomere length maintenance in the context of the ageing organism, we observed that DNA‐PKcs‐defective mice had a shorter life span and showed an earlier onset of ageing‐related pathologies than the corresponding wild‐type littermates. In addition, DNA‐PKcs ablation was associated with a markedly higher incidence of T lymphomas and infections. In conclusion, these data link the dual role of DNA‐PKcs in DNA repair and telomere length maintenance to organismal ageing and cancer.</abstract><cop>Chichester, UK</cop><pub>John Wiley & Sons, Ltd</pub><pmid>15105825</pmid><doi>10.1038/sj.embor.7400127</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Wiley Free Content; PubMed Central |
| subjects | ageing Aging - genetics Aging - physiology Animals Body Weight cancer Cell Cycle Chromosomes - metabolism Chromosomes - ultrastructure Deoxyribonucleic acid DNA DNA Damage DNA Repair DNA-Activated Protein Kinase DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism DNA-PKcs Female Life Expectancy Life span Lymphoma Lymphoma - genetics Lymphoma - metabolism Male Mammals Meiosis Mice Mice, Inbred C57BL Mice, Knockout Nuclear Proteins Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Scientific Report Spine - abnormalities Telomere - metabolism telomeres Testis - cytology |
| title | Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice |
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