Targeted DNA damage at individual telomeres disrupts their integrity and triggers cell death
Cellular DNA is organized into chromosomes and capped by a unique nucleoprotein structure, the telomere. Both oxidative stress and telomere shortening/dysfunction cause aging-related degenerative pathologies and increase cancer risk. However, a direct connection between oxidative damage to telomeric...
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| Veröffentlicht in: | Nucleic acids research 2015-07, Vol.43 (13), p.6334-6347 |
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| container_title | Nucleic acids research |
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| creator | Sun, Luxi Tan, Rong Xu, Jianquan LaFace, Justin Gao, Ying Xiao, Yanchun Attar, Myriam Neumann, Carola Li, Guo-Min Su, Bing Liu, Yang Nakajima, Satoshi Levine, Arthur S Lan, Li |
| description | Cellular DNA is organized into chromosomes and capped by a unique nucleoprotein structure, the telomere. Both oxidative stress and telomere shortening/dysfunction cause aging-related degenerative pathologies and increase cancer risk. However, a direct connection between oxidative damage to telomeric DNA, comprising |
| doi_str_mv | 10.1093/nar/gkv598 |
| format | Article |
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Both oxidative stress and telomere shortening/dysfunction cause aging-related degenerative pathologies and increase cancer risk. However, a direct connection between oxidative damage to telomeric DNA, comprising <1% of the genome, and telomere dysfunction has not been established. By fusing the KillerRed chromophore with the telomere repeat binding factor 1, TRF1, we developed a novel approach to generate localized damage to telomere DNA and to monitor the real time damage response at the single telomere level. We found that DNA damage at long telomeres in U2OS cells is not repaired efficiently compared to DNA damage in non-telomeric regions of the same length in heterochromatin. Telomeric DNA damage shortens the average length of telomeres and leads to cell senescence in HeLa cells and cell death in HeLa, U2OS and IMR90 cells, when DNA damage at non-telomeric regions is undetectable. Telomere-specific damage induces chromosomal aberrations, including chromatid telomere loss and telomere associations, distinct from the damage induced by ionizing irradiation. Taken together, our results demonstrate that oxidative damage induces telomere dysfunction and underline the importance of maintaining telomere integrity upon oxidative damage.</description><identifier>ISSN: 0305-1048</identifier><identifier>EISSN: 1362-4962</identifier><identifier>DOI: 10.1093/nar/gkv598</identifier><identifier>PMID: 26082495</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Cell Death ; Cell Line ; Cellular Senescence ; DNA Damage ; DNA Repair ; Genome Integrity, Repair and ; Green Fluorescent Proteins - genetics ; Guanine - analogs & derivatives ; Guanine - metabolism ; Humans ; Oxidative Stress ; Repetitive Sequences, Nucleic Acid ; Telomere - chemistry ; Telomere - metabolism ; Telomere Shortening ; Telomeric Repeat Binding Protein 1 - genetics</subject><ispartof>Nucleic acids research, 2015-07, Vol.43 (13), p.6334-6347</ispartof><rights>The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.</rights><rights>The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research. 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c411t-ec0b9be4848c50fb939ff6c0cd55df8da8bb00b9730d7898f18f932349aabdc93</citedby><cites>FETCH-LOGICAL-c411t-ec0b9be4848c50fb939ff6c0cd55df8da8bb00b9730d7898f18f932349aabdc93</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/PMC4513870/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513870/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26082495$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sun, Luxi</creatorcontrib><creatorcontrib>Tan, Rong</creatorcontrib><creatorcontrib>Xu, Jianquan</creatorcontrib><creatorcontrib>LaFace, Justin</creatorcontrib><creatorcontrib>Gao, Ying</creatorcontrib><creatorcontrib>Xiao, Yanchun</creatorcontrib><creatorcontrib>Attar, Myriam</creatorcontrib><creatorcontrib>Neumann, Carola</creatorcontrib><creatorcontrib>Li, Guo-Min</creatorcontrib><creatorcontrib>Su, Bing</creatorcontrib><creatorcontrib>Liu, Yang</creatorcontrib><creatorcontrib>Nakajima, Satoshi</creatorcontrib><creatorcontrib>Levine, Arthur S</creatorcontrib><creatorcontrib>Lan, Li</creatorcontrib><title>Targeted DNA damage at individual telomeres disrupts their integrity and triggers cell death</title><title>Nucleic acids research</title><addtitle>Nucleic Acids Res</addtitle><description>Cellular DNA is organized into chromosomes and capped by a unique nucleoprotein structure, the telomere. Both oxidative stress and telomere shortening/dysfunction cause aging-related degenerative pathologies and increase cancer risk. However, a direct connection between oxidative damage to telomeric DNA, comprising <1% of the genome, and telomere dysfunction has not been established. By fusing the KillerRed chromophore with the telomere repeat binding factor 1, TRF1, we developed a novel approach to generate localized damage to telomere DNA and to monitor the real time damage response at the single telomere level. We found that DNA damage at long telomeres in U2OS cells is not repaired efficiently compared to DNA damage in non-telomeric regions of the same length in heterochromatin. Telomeric DNA damage shortens the average length of telomeres and leads to cell senescence in HeLa cells and cell death in HeLa, U2OS and IMR90 cells, when DNA damage at non-telomeric regions is undetectable. Telomere-specific damage induces chromosomal aberrations, including chromatid telomere loss and telomere associations, distinct from the damage induced by ionizing irradiation. Taken together, our results demonstrate that oxidative damage induces telomere dysfunction and underline the importance of maintaining telomere integrity upon oxidative damage.</description><subject>Cell Death</subject><subject>Cell Line</subject><subject>Cellular Senescence</subject><subject>DNA Damage</subject><subject>DNA Repair</subject><subject>Genome Integrity, Repair and</subject><subject>Green Fluorescent Proteins - genetics</subject><subject>Guanine - analogs & derivatives</subject><subject>Guanine - metabolism</subject><subject>Humans</subject><subject>Oxidative Stress</subject><subject>Repetitive Sequences, Nucleic Acid</subject><subject>Telomere - chemistry</subject><subject>Telomere - metabolism</subject><subject>Telomere Shortening</subject><subject>Telomeric Repeat Binding Protein 1 - genetics</subject><issn>0305-1048</issn><issn>1362-4962</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkUtLBDEQhIMouj4u_gDJUYTRZJLsJBdB1icsellvQsgkPbPReaxJZsF_78iq6KkP_VHVXYXQMSXnlCh20ZlwUb-thZJbaELZNM-4mubbaEIYERklXO6h_RhfCaGcCr6L9vIpkTlXYoJeFibUkMDh68cr7ExrasAmYd85v_ZuMA1O0PQtBIjY-RiGVYo4LcGHkUlQB58-sOkcTsHXNYSILTQNdmDS8hDtVKaJcPQ9D9Dz7c1idp_Nn-4eZlfzzHJKUwaWlKoELrm0glSlYqqqppZYJ4SrpDOyLMmIFIy4QipZUVkpljOujCmdVewAXW50V0PZgrPQpWAavQq-NeFD98br_5vOL3XdrzUXlMmCjAKn3wKhfx8gJt36-PWH6aAfoqYFzcVoX_ARPdugNvQxBqh-bSjRX3XosQ69qWOET_4e9ov-5M8-AeX-iec</recordid><startdate>20150727</startdate><enddate>20150727</enddate><creator>Sun, Luxi</creator><creator>Tan, Rong</creator><creator>Xu, Jianquan</creator><creator>LaFace, Justin</creator><creator>Gao, Ying</creator><creator>Xiao, Yanchun</creator><creator>Attar, Myriam</creator><creator>Neumann, Carola</creator><creator>Li, Guo-Min</creator><creator>Su, Bing</creator><creator>Liu, Yang</creator><creator>Nakajima, Satoshi</creator><creator>Levine, Arthur S</creator><creator>Lan, Li</creator><general>Oxford University Press</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>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20150727</creationdate><title>Targeted DNA damage at individual telomeres disrupts their integrity and triggers cell death</title><author>Sun, Luxi ; Tan, Rong ; Xu, Jianquan ; LaFace, Justin ; Gao, Ying ; Xiao, Yanchun ; Attar, Myriam ; Neumann, Carola ; Li, Guo-Min ; Su, Bing ; Liu, Yang ; Nakajima, Satoshi ; Levine, Arthur S ; Lan, Li</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c411t-ec0b9be4848c50fb939ff6c0cd55df8da8bb00b9730d7898f18f932349aabdc93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Cell Death</topic><topic>Cell Line</topic><topic>Cellular Senescence</topic><topic>DNA Damage</topic><topic>DNA Repair</topic><topic>Genome Integrity, Repair and</topic><topic>Green Fluorescent Proteins - genetics</topic><topic>Guanine - analogs & derivatives</topic><topic>Guanine - metabolism</topic><topic>Humans</topic><topic>Oxidative Stress</topic><topic>Repetitive Sequences, Nucleic Acid</topic><topic>Telomere - chemistry</topic><topic>Telomere - metabolism</topic><topic>Telomere Shortening</topic><topic>Telomeric Repeat Binding Protein 1 - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sun, Luxi</creatorcontrib><creatorcontrib>Tan, Rong</creatorcontrib><creatorcontrib>Xu, Jianquan</creatorcontrib><creatorcontrib>LaFace, Justin</creatorcontrib><creatorcontrib>Gao, Ying</creatorcontrib><creatorcontrib>Xiao, Yanchun</creatorcontrib><creatorcontrib>Attar, Myriam</creatorcontrib><creatorcontrib>Neumann, Carola</creatorcontrib><creatorcontrib>Li, Guo-Min</creatorcontrib><creatorcontrib>Su, Bing</creatorcontrib><creatorcontrib>Liu, Yang</creatorcontrib><creatorcontrib>Nakajima, Satoshi</creatorcontrib><creatorcontrib>Levine, Arthur S</creatorcontrib><creatorcontrib>Lan, Li</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nucleic acids research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sun, Luxi</au><au>Tan, Rong</au><au>Xu, Jianquan</au><au>LaFace, Justin</au><au>Gao, Ying</au><au>Xiao, Yanchun</au><au>Attar, Myriam</au><au>Neumann, Carola</au><au>Li, Guo-Min</au><au>Su, Bing</au><au>Liu, Yang</au><au>Nakajima, Satoshi</au><au>Levine, Arthur S</au><au>Lan, Li</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeted DNA damage at individual telomeres disrupts their integrity and triggers cell death</atitle><jtitle>Nucleic acids research</jtitle><addtitle>Nucleic Acids Res</addtitle><date>2015-07-27</date><risdate>2015</risdate><volume>43</volume><issue>13</issue><spage>6334</spage><epage>6347</epage><pages>6334-6347</pages><issn>0305-1048</issn><eissn>1362-4962</eissn><abstract>Cellular DNA is organized into chromosomes and capped by a unique nucleoprotein structure, the telomere. Both oxidative stress and telomere shortening/dysfunction cause aging-related degenerative pathologies and increase cancer risk. However, a direct connection between oxidative damage to telomeric DNA, comprising <1% of the genome, and telomere dysfunction has not been established. By fusing the KillerRed chromophore with the telomere repeat binding factor 1, TRF1, we developed a novel approach to generate localized damage to telomere DNA and to monitor the real time damage response at the single telomere level. We found that DNA damage at long telomeres in U2OS cells is not repaired efficiently compared to DNA damage in non-telomeric regions of the same length in heterochromatin. Telomeric DNA damage shortens the average length of telomeres and leads to cell senescence in HeLa cells and cell death in HeLa, U2OS and IMR90 cells, when DNA damage at non-telomeric regions is undetectable. Telomere-specific damage induces chromosomal aberrations, including chromatid telomere loss and telomere associations, distinct from the damage induced by ionizing irradiation. Taken together, our results demonstrate that oxidative damage induces telomere dysfunction and underline the importance of maintaining telomere integrity upon oxidative damage.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>26082495</pmid><doi>10.1093/nar/gkv598</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Nucleic acids research, 2015-07, Vol.43 (13), p.6334-6347 |
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| source | Oxford Journals Open Access Collection; MEDLINE; DOAJ Directory of Open Access Journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Cell Death Cell Line Cellular Senescence DNA Damage DNA Repair Genome Integrity, Repair and Green Fluorescent Proteins - genetics Guanine - analogs & derivatives Guanine - metabolism Humans Oxidative Stress Repetitive Sequences, Nucleic Acid Telomere - chemistry Telomere - metabolism Telomere Shortening Telomeric Repeat Binding Protein 1 - genetics |
| title | Targeted DNA damage at individual telomeres disrupts their integrity and triggers cell death |
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