RTEL1 Is a Replisome-Associated Helicase That Promotes Telomere and Genome-Wide Replication
Regulator of telomere length 1 (RTEL1) is an essential DNA helicase that disassembles telomere loops (T loops) and suppresses telomere fragility to maintain the integrity of chromosome ends. We established that RTEL1 also associates with the replisome through binding to proliferating cell nuclear an...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2013-10, Vol.342 (6155), p.239-242 |
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| creator | Vannier, Jean-Baptiste Sandhu, Sumit Petalcorin, Mark IR Wu, Xiaoli Nabi, Zinnatun Ding, Hao Boulton, Simon J. |
| description | Regulator of telomere length 1 (RTEL1) is an essential DNA helicase that disassembles telomere loops (T loops) and suppresses telomere fragility to maintain the integrity of chromosome ends. We established that RTEL1 also associates with the replisome through binding to proliferating cell nuclear antigen (PCNA). Mouse cells disrupted for the RTEL1-PCNA interaction (PIP mutant) exhibited accelerated senescence, replication fork instability, reduced replication fork extension rates, and increased origin usage. Although T-loop disassembly at telomeres was unaffected in the mutant cells, telomere replication was compromised, leading to fragile sites at telomeres. RTEL1-PIP mutant mice were viable, but loss of the RTEL1-PCNA interaction accelerated the onset of tumorigenesis in p53-deficient mice. We propose that RTEL1 plays a critical role in both telomere and genome-wide replication, which is crucial for genetic stability and tumor avoidance. |
| doi_str_mv | 10.1126/science.1241779 |
| format | Article |
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We established that RTEL1 also associates with the replisome through binding to proliferating cell nuclear antigen (PCNA). Mouse cells disrupted for the RTEL1-PCNA interaction (PIP mutant) exhibited accelerated senescence, replication fork instability, reduced replication fork extension rates, and increased origin usage. Although T-loop disassembly at telomeres was unaffected in the mutant cells, telomere replication was compromised, leading to fragile sites at telomeres. RTEL1-PIP mutant mice were viable, but loss of the RTEL1-PCNA interaction accelerated the onset of tumorigenesis in p53-deficient mice. We propose that RTEL1 plays a critical role in both telomere and genome-wide replication, which is crucial for genetic stability and tumor avoidance.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.1241779</identifier><identifier>PMID: 24115439</identifier><identifier>CODEN: SCIEAS</identifier><language>eng</language><publisher>United States: American Association for the Advancement of Science</publisher><subject>Animals ; Antigens ; Byproducts ; Cell cycle ; Cell Line ; Cell Transformation, Neoplastic - genetics ; Cell Transformation, Neoplastic - metabolism ; Deoxyribonucleic acid ; Dismantling ; DNA ; DNA damage ; DNA Helicases - genetics ; DNA Helicases - metabolism ; DNA Replication ; Enzymes ; Genome - genetics ; Genomics ; HeLa cells ; Mammals ; Metaphase ; Mice ; Mice, Mutant Strains ; Proliferating Cell Nuclear Antigen - metabolism ; Proteins ; Quantification ; Regulators ; Replication ; Research facilities ; Stability ; Telomere - genetics ; Telomeres ; Tumor Suppressor Protein p53 - genetics ; Tumors</subject><ispartof>Science (American Association for the Advancement of Science), 2013-10, Vol.342 (6155), p.239-242</ispartof><rights>Copyright © 2013 American Association for the Advancement of Science</rights><rights>Copyright © 2013, American Association for the Advancement of Science</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c413t-2cd37b6964f0de8bc0b0a8998b69ab925597909569cd5c7ed15d8edd9d956f493</citedby><cites>FETCH-LOGICAL-c413t-2cd37b6964f0de8bc0b0a8998b69ab925597909569cd5c7ed15d8edd9d956f493</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/42619826$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/42619826$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>314,780,784,803,2883,2884,27923,27924,58016,58249</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24115439$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vannier, Jean-Baptiste</creatorcontrib><creatorcontrib>Sandhu, Sumit</creatorcontrib><creatorcontrib>Petalcorin, Mark IR</creatorcontrib><creatorcontrib>Wu, Xiaoli</creatorcontrib><creatorcontrib>Nabi, Zinnatun</creatorcontrib><creatorcontrib>Ding, Hao</creatorcontrib><creatorcontrib>Boulton, Simon J.</creatorcontrib><title>RTEL1 Is a Replisome-Associated Helicase That Promotes Telomere and Genome-Wide Replication</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>Regulator of telomere length 1 (RTEL1) is an essential DNA helicase that disassembles telomere loops (T loops) and suppresses telomere fragility to maintain the integrity of chromosome ends. 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We established that RTEL1 also associates with the replisome through binding to proliferating cell nuclear antigen (PCNA). Mouse cells disrupted for the RTEL1-PCNA interaction (PIP mutant) exhibited accelerated senescence, replication fork instability, reduced replication fork extension rates, and increased origin usage. Although T-loop disassembly at telomeres was unaffected in the mutant cells, telomere replication was compromised, leading to fragile sites at telomeres. RTEL1-PIP mutant mice were viable, but loss of the RTEL1-PCNA interaction accelerated the onset of tumorigenesis in p53-deficient mice. We propose that RTEL1 plays a critical role in both telomere and genome-wide replication, which is crucial for genetic stability and tumor avoidance.</abstract><cop>United States</cop><pub>American Association for the Advancement of Science</pub><pmid>24115439</pmid><doi>10.1126/science.1241779</doi><tpages>4</tpages></addata></record> |
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| ispartof | Science (American Association for the Advancement of Science), 2013-10, Vol.342 (6155), p.239-242 |
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| source | MEDLINE; JSTOR Archive Collection A-Z Listing; American Association for the Advancement of Science |
| subjects | Animals Antigens Byproducts Cell cycle Cell Line Cell Transformation, Neoplastic - genetics Cell Transformation, Neoplastic - metabolism Deoxyribonucleic acid Dismantling DNA DNA damage DNA Helicases - genetics DNA Helicases - metabolism DNA Replication Enzymes Genome - genetics Genomics HeLa cells Mammals Metaphase Mice Mice, Mutant Strains Proliferating Cell Nuclear Antigen - metabolism Proteins Quantification Regulators Replication Research facilities Stability Telomere - genetics Telomeres Tumor Suppressor Protein p53 - genetics Tumors |
| title | RTEL1 Is a Replisome-Associated Helicase That Promotes Telomere and Genome-Wide Replication |
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