Human RECQ1 interacts with Ku70/80 and modulates DNA end-joining of double-strand breaks
Genomic instability is a known precursor to cancer and aging. The RecQ helicases are a highly conserved family of DNA-unwinding enzymes that play key roles in maintaining genome stability in all living organisms. Human RecQ homologs include RECQ1, BLM, WRN, RECQ4, and RECQ5β, three of which have bee...
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| description | Genomic instability is a known precursor to cancer and aging. The RecQ helicases are a highly conserved family of DNA-unwinding enzymes that play key roles in maintaining genome stability in all living organisms. Human RecQ homologs include RECQ1, BLM, WRN, RECQ4, and RECQ5β, three of which have been linked to diseases with elevated risk of cancer and growth defects (Bloom Syndrome and Rothmund-Thomson Syndrome) or premature aging (Werner Syndrome). RECQ1, the first RecQ helicase discovered and the most abundant in human cells, is the least well understood of the five human RecQ homologs. We have previously described that knockout of RECQ1 in mice or knockdown of its expression in human cells results in elevated frequency of spontaneous sister chromatid exchanges, chromosomal instability, increased load of DNA damage and heightened sensitivity to ionizing radiation. We have now obtained evidence implicating RECQ1 in the nonhomologous end-joining pathway of DNA double-strand break repair. We show that RECQ1 interacts directly with the Ku70/80 subunit of the DNA-PK complex, and depletion of RECQ1 results in reduced end-joining in cell free extracts. In vitro, RECQ1 binds and unwinds the Ku70/80-bound partial duplex DNA substrate efficiently. Linear DNA is co-bound by RECQ1 and Ku70/80, and DNA binding by Ku70/80 is modulated by RECQ1. Collectively, these results provide the first evidence for an interaction of RECQ1 with Ku70/80 and a role of the human RecQ helicase in double-strand break repair through nonhomologous end-joining. |
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The RecQ helicases are a highly conserved family of DNA-unwinding enzymes that play key roles in maintaining genome stability in all living organisms. Human RecQ homologs include RECQ1, BLM, WRN, RECQ4, and RECQ5β, three of which have been linked to diseases with elevated risk of cancer and growth defects (Bloom Syndrome and Rothmund-Thomson Syndrome) or premature aging (Werner Syndrome). RECQ1, the first RecQ helicase discovered and the most abundant in human cells, is the least well understood of the five human RecQ homologs. We have previously described that knockout of RECQ1 in mice or knockdown of its expression in human cells results in elevated frequency of spontaneous sister chromatid exchanges, chromosomal instability, increased load of DNA damage and heightened sensitivity to ionizing radiation. We have now obtained evidence implicating RECQ1 in the nonhomologous end-joining pathway of DNA double-strand break repair. We show that RECQ1 interacts directly with the Ku70/80 subunit of the DNA-PK complex, and depletion of RECQ1 results in reduced end-joining in cell free extracts. In vitro, RECQ1 binds and unwinds the Ku70/80-bound partial duplex DNA substrate efficiently. Linear DNA is co-bound by RECQ1 and Ku70/80, and DNA binding by Ku70/80 is modulated by RECQ1. Collectively, these results provide the first evidence for an interaction of RECQ1 with Ku70/80 and a role of the human RecQ helicase in double-strand break repair through nonhomologous end-joining.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0062481</identifier><identifier>PMID: 23650516</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aging ; Antigens, Nuclear - chemistry ; Antigens, Nuclear - metabolism ; Biology ; Bloom's syndrome ; Cancer ; Chromosomes ; Defects ; Deoxyribonucleic acid ; DNA ; DNA - chemistry ; DNA Breaks, Double-Stranded ; DNA damage ; DNA End-Joining Repair ; DNA helicase ; DNA repair ; DNA-Binding Proteins - chemistry ; DNA-Binding Proteins - metabolism ; DNA-dependent protein kinase ; Double-strand break repair ; Electrophoretic Mobility Shift Assay ; Frequency stability ; Genomes ; Genomic instability ; Health aspects ; Health risks ; HeLa Cells ; Helicases ; Homology ; Humans ; Ionizing radiation ; Kinases ; Ku Autoantigen ; Laboratories ; Nucleic Acid Conformation ; Oligonucleotides - chemistry ; Protein Binding ; Protein Interaction Maps ; Radiation ; Radiation damage ; RecQ Helicases - chemistry ; RecQ Helicases - metabolism ; RecQ protein ; Repair ; Rothmund-Thomson syndrome ; Substrates ; Unwinding ; Werner's syndrome</subject><ispartof>PloS one, 2013-05, Vol.8 (5), p.e62481-e62481</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013. This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-548b85e5b3fc448108ad4487dd0aaf69088ddc05cd3d7ae276ac49262a522a0d3</citedby><cites>FETCH-LOGICAL-c692t-548b85e5b3fc448108ad4487dd0aaf69088ddc05cd3d7ae276ac49262a522a0d3</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/PMC3641083/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641083/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2914,23846,27903,27904,53770,53772,79347,79348</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23650516$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Borgmann, Kerstin</contributor><creatorcontrib>Parvathaneni, Swetha</creatorcontrib><creatorcontrib>Stortchevoi, Alexei</creatorcontrib><creatorcontrib>Sommers, Joshua A</creatorcontrib><creatorcontrib>Brosh, Jr, Robert M</creatorcontrib><creatorcontrib>Sharma, Sudha</creatorcontrib><title>Human RECQ1 interacts with Ku70/80 and modulates DNA end-joining of double-strand breaks</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Genomic instability is a known precursor to cancer and aging. The RecQ helicases are a highly conserved family of DNA-unwinding enzymes that play key roles in maintaining genome stability in all living organisms. Human RecQ homologs include RECQ1, BLM, WRN, RECQ4, and RECQ5β, three of which have been linked to diseases with elevated risk of cancer and growth defects (Bloom Syndrome and Rothmund-Thomson Syndrome) or premature aging (Werner Syndrome). RECQ1, the first RecQ helicase discovered and the most abundant in human cells, is the least well understood of the five human RecQ homologs. We have previously described that knockout of RECQ1 in mice or knockdown of its expression in human cells results in elevated frequency of spontaneous sister chromatid exchanges, chromosomal instability, increased load of DNA damage and heightened sensitivity to ionizing radiation. We have now obtained evidence implicating RECQ1 in the nonhomologous end-joining pathway of DNA double-strand break repair. We show that RECQ1 interacts directly with the Ku70/80 subunit of the DNA-PK complex, and depletion of RECQ1 results in reduced end-joining in cell free extracts. In vitro, RECQ1 binds and unwinds the Ku70/80-bound partial duplex DNA substrate efficiently. Linear DNA is co-bound by RECQ1 and Ku70/80, and DNA binding by Ku70/80 is modulated by RECQ1. Collectively, these results provide the first evidence for an interaction of RECQ1 with Ku70/80 and a role of the human RecQ helicase in double-strand break repair through nonhomologous end-joining.</description><subject>Aging</subject><subject>Antigens, Nuclear - chemistry</subject><subject>Antigens, Nuclear - metabolism</subject><subject>Biology</subject><subject>Bloom's syndrome</subject><subject>Cancer</subject><subject>Chromosomes</subject><subject>Defects</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA - chemistry</subject><subject>DNA Breaks, Double-Stranded</subject><subject>DNA damage</subject><subject>DNA End-Joining Repair</subject><subject>DNA helicase</subject><subject>DNA repair</subject><subject>DNA-Binding Proteins - chemistry</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>DNA-dependent protein kinase</subject><subject>Double-strand break repair</subject><subject>Electrophoretic Mobility Shift Assay</subject><subject>Frequency stability</subject><subject>Genomes</subject><subject>Genomic instability</subject><subject>Health aspects</subject><subject>Health risks</subject><subject>HeLa Cells</subject><subject>Helicases</subject><subject>Homology</subject><subject>Humans</subject><subject>Ionizing radiation</subject><subject>Kinases</subject><subject>Ku Autoantigen</subject><subject>Laboratories</subject><subject>Nucleic Acid Conformation</subject><subject>Oligonucleotides - chemistry</subject><subject>Protein Binding</subject><subject>Protein Interaction Maps</subject><subject>Radiation</subject><subject>Radiation damage</subject><subject>RecQ Helicases - chemistry</subject><subject>RecQ Helicases - metabolism</subject><subject>RecQ protein</subject><subject>Repair</subject><subject>Rothmund-Thomson syndrome</subject><subject>Substrates</subject><subject>Unwinding</subject><subject>Werner's syndrome</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</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>eNqNk9tu1DAQhiMEogd4AwSRkBBcZOvYsZPcIK22ha6oqCgHcWdNbGfX28ReYofD2-N002qDeoF8Ycv-5h__Y08UPUvRLCV5erKxfWegmW2tUTOEGM6K9EF0mJYEJwwj8nBvfRAdObdBiJKCscfRASaMIpqyw-j7ed-Cia_OFp_SWBuvOhDexb-0X8cf-hydFCgGI-PWyr4Br1x8-nEeKyOTjdVGm1Vs61javmpU4nw3oFWn4No9iR7V0Dj1dJyPo6_vzr4szpOLy_fLxfwiEazEPqFZURVU0YrUIgsOUAEyzLmUCKBmJSoKKQWiQhKZg8I5A5GVmGGgGAOS5Dh6sdPdNtbxsSiOpySIYZwiFojljpAWNnzb6Ra6P9yC5jcbtltx6LwWjeJlUdWopkWJpMgUkqCoykVNQ3pW0mrQejtm66tWSaFM8NxMRKcnRq_5yv7khGXBGwkCr0eBzv7olfO81U6opgGjbH9z7zJDqCQooC__Qe93N1IrCAa0qW3IKwZRPs_yYqhlOWjN7qHCkKrVIvygWof9ScCbSUBgvPrtV9A7x5efr_6fvfw2ZV_tsWsFjV872_ReW-OmYLYDRWed61R9V-QU8aEBbqvBhwbgYwOEsOf7D3QXdPvjyV9z6v5o</recordid><startdate>20130501</startdate><enddate>20130501</enddate><creator>Parvathaneni, Swetha</creator><creator>Stortchevoi, Alexei</creator><creator>Sommers, Joshua A</creator><creator>Brosh, Jr, Robert M</creator><creator>Sharma, Sudha</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>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</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>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20130501</creationdate><title>Human RECQ1 interacts with Ku70/80 and modulates DNA end-joining of double-strand breaks</title><author>Parvathaneni, Swetha ; Stortchevoi, Alexei ; Sommers, Joshua A ; Brosh, Jr, Robert M ; Sharma, Sudha</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-548b85e5b3fc448108ad4487dd0aaf69088ddc05cd3d7ae276ac49262a522a0d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Aging</topic><topic>Antigens, Nuclear - chemistry</topic><topic>Antigens, Nuclear - metabolism</topic><topic>Biology</topic><topic>Bloom's syndrome</topic><topic>Cancer</topic><topic>Chromosomes</topic><topic>Defects</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA - chemistry</topic><topic>DNA Breaks, Double-Stranded</topic><topic>DNA damage</topic><topic>DNA End-Joining Repair</topic><topic>DNA helicase</topic><topic>DNA repair</topic><topic>DNA-Binding Proteins - chemistry</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>DNA-dependent protein kinase</topic><topic>Double-strand break repair</topic><topic>Electrophoretic Mobility Shift Assay</topic><topic>Frequency stability</topic><topic>Genomes</topic><topic>Genomic instability</topic><topic>Health aspects</topic><topic>Health risks</topic><topic>HeLa Cells</topic><topic>Helicases</topic><topic>Homology</topic><topic>Humans</topic><topic>Ionizing radiation</topic><topic>Kinases</topic><topic>Ku Autoantigen</topic><topic>Laboratories</topic><topic>Nucleic Acid Conformation</topic><topic>Oligonucleotides - chemistry</topic><topic>Protein Binding</topic><topic>Protein Interaction Maps</topic><topic>Radiation</topic><topic>Radiation damage</topic><topic>RecQ Helicases - chemistry</topic><topic>RecQ Helicases - metabolism</topic><topic>RecQ protein</topic><topic>Repair</topic><topic>Rothmund-Thomson syndrome</topic><topic>Substrates</topic><topic>Unwinding</topic><topic>Werner's syndrome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Parvathaneni, Swetha</creatorcontrib><creatorcontrib>Stortchevoi, Alexei</creatorcontrib><creatorcontrib>Sommers, Joshua A</creatorcontrib><creatorcontrib>Brosh, Jr, Robert M</creatorcontrib><creatorcontrib>Sharma, Sudha</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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The RecQ helicases are a highly conserved family of DNA-unwinding enzymes that play key roles in maintaining genome stability in all living organisms. Human RecQ homologs include RECQ1, BLM, WRN, RECQ4, and RECQ5β, three of which have been linked to diseases with elevated risk of cancer and growth defects (Bloom Syndrome and Rothmund-Thomson Syndrome) or premature aging (Werner Syndrome). RECQ1, the first RecQ helicase discovered and the most abundant in human cells, is the least well understood of the five human RecQ homologs. We have previously described that knockout of RECQ1 in mice or knockdown of its expression in human cells results in elevated frequency of spontaneous sister chromatid exchanges, chromosomal instability, increased load of DNA damage and heightened sensitivity to ionizing radiation. We have now obtained evidence implicating RECQ1 in the nonhomologous end-joining pathway of DNA double-strand break repair. We show that RECQ1 interacts directly with the Ku70/80 subunit of the DNA-PK complex, and depletion of RECQ1 results in reduced end-joining in cell free extracts. In vitro, RECQ1 binds and unwinds the Ku70/80-bound partial duplex DNA substrate efficiently. Linear DNA is co-bound by RECQ1 and Ku70/80, and DNA binding by Ku70/80 is modulated by RECQ1. Collectively, these results provide the first evidence for an interaction of RECQ1 with Ku70/80 and a role of the human RecQ helicase in double-strand break repair through nonhomologous end-joining.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23650516</pmid><doi>10.1371/journal.pone.0062481</doi><tpages>e62481</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1932-6203 |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Aging Antigens, Nuclear - chemistry Antigens, Nuclear - metabolism Biology Bloom's syndrome Cancer Chromosomes Defects Deoxyribonucleic acid DNA DNA - chemistry DNA Breaks, Double-Stranded DNA damage DNA End-Joining Repair DNA helicase DNA repair DNA-Binding Proteins - chemistry DNA-Binding Proteins - metabolism DNA-dependent protein kinase Double-strand break repair Electrophoretic Mobility Shift Assay Frequency stability Genomes Genomic instability Health aspects Health risks HeLa Cells Helicases Homology Humans Ionizing radiation Kinases Ku Autoantigen Laboratories Nucleic Acid Conformation Oligonucleotides - chemistry Protein Binding Protein Interaction Maps Radiation Radiation damage RecQ Helicases - chemistry RecQ Helicases - metabolism RecQ protein Repair Rothmund-Thomson syndrome Substrates Unwinding Werner's syndrome |
| title | Human RECQ1 interacts with Ku70/80 and modulates DNA end-joining of double-strand breaks |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-22T01%3A49%3A20IST&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=Human%20RECQ1%20interacts%20with%20Ku70/80%20and%20modulates%20DNA%20end-joining%20of%20double-strand%20breaks&rft.jtitle=PloS%20one&rft.au=Parvathaneni,%20Swetha&rft.date=2013-05-01&rft.volume=8&rft.issue=5&rft.spage=e62481&rft.epage=e62481&rft.pages=e62481-e62481&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0062481&rft_dat=%3Cgale_plos_%3EA478448790%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=1348122106&rft_id=info:pmid/23650516&rft_galeid=A478448790&rft_doaj_id=oai_doaj_org_article_98bf0f5890dc4e0dae5e7cf55cd695b6&rfr_iscdi=true |