Excess Mcm2-7 license dormant origins of replication that can be used under conditions of replicative stress
In late mitosis and early G1, replication origins are licensed for subsequent use by loading complexes of the minichromosome maintenance proteins 2-7 (Mcm2-7). The number of Mcm2-7 complexes loaded onto DNA greatly exceeds the number of replication origins used during S phase, but the function of th...
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| Veröffentlicht in: | The Journal of cell biology 2006-06, Vol.173 (5), p.673-683 |
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| container_title | The Journal of cell biology |
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| creator | Woodward, Anna M Göhler, Thomas Luciani, M. Gloria Oehlmann, Maren Ge, Xinquan Gartner, Anton Jackson, Dean A Blow, J. Julian |
| description | In late mitosis and early G1, replication origins are licensed for subsequent use by loading complexes of the minichromosome maintenance proteins 2-7 (Mcm2-7). The number of Mcm2-7 complexes loaded onto DNA greatly exceeds the number of replication origins used during S phase, but the function of the excess Mcm2-7 is unknown. Using Xenopus laevis egg extracts, we show that these excess Mcm2-7 complexes license additional dormant origins that do not fire during unperturbed S phases because of suppression by a caffeine-sensitive checkpoint pathway. Use of these additional origins can allow complete genome replication in the presence of replication inhibitors. These results suggest that metazoan replication origins are actually comprised of several candidate origins, most of which normally remain dormant unless cells experience replicative stress. Consistent with this model, using Caenorhabditis elegans, we show that partial RNAi-based knockdown of MCMs that has no observable effect under normal conditions causes lethality upon treatment with low, otherwise nontoxic, levels of the replication inhibitor hydroxyurea. |
| doi_str_mv | 10.1083/jcb.200602108 |
| format | Article |
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Gloria ; Oehlmann, Maren ; Ge, Xinquan ; Gartner, Anton ; Jackson, Dean A ; Blow, J. Julian</creator><creatorcontrib>Woodward, Anna M ; Göhler, Thomas ; Luciani, M. Gloria ; Oehlmann, Maren ; Ge, Xinquan ; Gartner, Anton ; Jackson, Dean A ; Blow, J. Julian</creatorcontrib><description>In late mitosis and early G1, replication origins are licensed for subsequent use by loading complexes of the minichromosome maintenance proteins 2-7 (Mcm2-7). The number of Mcm2-7 complexes loaded onto DNA greatly exceeds the number of replication origins used during S phase, but the function of the excess Mcm2-7 is unknown. Using Xenopus laevis egg extracts, we show that these excess Mcm2-7 complexes license additional dormant origins that do not fire during unperturbed S phases because of suppression by a caffeine-sensitive checkpoint pathway. Use of these additional origins can allow complete genome replication in the presence of replication inhibitors. These results suggest that metazoan replication origins are actually comprised of several candidate origins, most of which normally remain dormant unless cells experience replicative stress. Consistent with this model, using Caenorhabditis elegans, we show that partial RNAi-based knockdown of MCMs that has no observable effect under normal conditions causes lethality upon treatment with low, otherwise nontoxic, levels of the replication inhibitor hydroxyurea.</description><identifier>ISSN: 0021-9525</identifier><identifier>EISSN: 1540-8140</identifier><identifier>DOI: 10.1083/jcb.200602108</identifier><identifier>PMID: 16754955</identifier><language>eng</language><publisher>United States: The Rockefeller University Press</publisher><subject>Adenosine Triphosphatases - drug effects ; Adenosine Triphosphatases - metabolism ; Animals ; Aphidicolin - pharmacology ; Caenorhabditis elegans ; Caenorhabditis elegans - drug effects ; Caenorhabditis elegans - growth & development ; Caffeine - pharmacology ; Carrier Proteins - drug effects ; Carrier Proteins - metabolism ; Cell Cycle Proteins - drug effects ; Cell Cycle Proteins - metabolism ; Cell Survival - drug effects ; Chromatin ; Chromatin - drug effects ; Chromatin - metabolism ; DNA ; DNA replication ; DNA Replication - drug effects ; DNA Replication - physiology ; DNA-Binding Proteins - drug effects ; DNA-Binding Proteins - metabolism ; Gels ; Hydroxyurea - pharmacology ; Interphase ; Metazoa ; Minichromosome Maintenance Complex Component 2 ; Minichromosome Maintenance Complex Component 3 ; Minichromosome Maintenance Complex Component 4 ; Minichromosome Maintenance Complex Component 7 ; Molecules ; Nuclear Proteins - drug effects ; Nuclear Proteins - metabolism ; Ova ; Oxidative Stress - physiology ; Replication Origin ; Small interfering RNA ; Spermatozoa ; Time Factors ; Xenopus laevis ; Xenopus Proteins - drug effects ; Xenopus Proteins - metabolism</subject><ispartof>The Journal of cell biology, 2006-06, Vol.173 (5), p.673-683</ispartof><rights>Copyright 2006 The Rockefeller University Press</rights><rights>Copyright © 2006, The Rockefeller University Press 2006</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c461t-9e20f8449ca27b29ad275e09ab23a241d56e4e1a78e31105fe9197718044024c3</citedby><cites>FETCH-LOGICAL-c461t-9e20f8449ca27b29ad275e09ab23a241d56e4e1a78e31105fe9197718044024c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,777,781,882,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16754955$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Woodward, Anna M</creatorcontrib><creatorcontrib>Göhler, Thomas</creatorcontrib><creatorcontrib>Luciani, M. Gloria</creatorcontrib><creatorcontrib>Oehlmann, Maren</creatorcontrib><creatorcontrib>Ge, Xinquan</creatorcontrib><creatorcontrib>Gartner, Anton</creatorcontrib><creatorcontrib>Jackson, Dean A</creatorcontrib><creatorcontrib>Blow, J. Julian</creatorcontrib><title>Excess Mcm2-7 license dormant origins of replication that can be used under conditions of replicative stress</title><title>The Journal of cell biology</title><addtitle>J Cell Biol</addtitle><description>In late mitosis and early G1, replication origins are licensed for subsequent use by loading complexes of the minichromosome maintenance proteins 2-7 (Mcm2-7). The number of Mcm2-7 complexes loaded onto DNA greatly exceeds the number of replication origins used during S phase, but the function of the excess Mcm2-7 is unknown. Using Xenopus laevis egg extracts, we show that these excess Mcm2-7 complexes license additional dormant origins that do not fire during unperturbed S phases because of suppression by a caffeine-sensitive checkpoint pathway. Use of these additional origins can allow complete genome replication in the presence of replication inhibitors. These results suggest that metazoan replication origins are actually comprised of several candidate origins, most of which normally remain dormant unless cells experience replicative stress. Consistent with this model, using Caenorhabditis elegans, we show that partial RNAi-based knockdown of MCMs that has no observable effect under normal conditions causes lethality upon treatment with low, otherwise nontoxic, levels of the replication inhibitor hydroxyurea.</description><subject>Adenosine Triphosphatases - drug effects</subject><subject>Adenosine Triphosphatases - metabolism</subject><subject>Animals</subject><subject>Aphidicolin - pharmacology</subject><subject>Caenorhabditis elegans</subject><subject>Caenorhabditis elegans - drug effects</subject><subject>Caenorhabditis elegans - growth & development</subject><subject>Caffeine - pharmacology</subject><subject>Carrier Proteins - drug effects</subject><subject>Carrier Proteins - metabolism</subject><subject>Cell Cycle Proteins - drug effects</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>Cell Survival - drug effects</subject><subject>Chromatin</subject><subject>Chromatin - drug effects</subject><subject>Chromatin - metabolism</subject><subject>DNA</subject><subject>DNA replication</subject><subject>DNA Replication - drug effects</subject><subject>DNA Replication - physiology</subject><subject>DNA-Binding Proteins - drug effects</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Gels</subject><subject>Hydroxyurea - pharmacology</subject><subject>Interphase</subject><subject>Metazoa</subject><subject>Minichromosome Maintenance Complex Component 2</subject><subject>Minichromosome Maintenance Complex Component 3</subject><subject>Minichromosome Maintenance Complex Component 4</subject><subject>Minichromosome Maintenance Complex Component 7</subject><subject>Molecules</subject><subject>Nuclear Proteins - drug effects</subject><subject>Nuclear Proteins - metabolism</subject><subject>Ova</subject><subject>Oxidative Stress - physiology</subject><subject>Replication Origin</subject><subject>Small interfering RNA</subject><subject>Spermatozoa</subject><subject>Time Factors</subject><subject>Xenopus laevis</subject><subject>Xenopus Proteins - drug effects</subject><subject>Xenopus Proteins - metabolism</subject><issn>0021-9525</issn><issn>1540-8140</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkUtv1DAURi0EokNhyQ6BV-xSrl9xskGqqvKQilhA15bj3Ew9SuzBdir497ia0UBXln2Ov2vrI-Q1gwsGnfiwc8MFB2iB1-0TsmFKQtMxCU_JBuph0yuuzsiLnHcAILUUz8kZa7WSvVIbMl__dpgz_eYW3mg6e4chIx1jWmwoNCa_9SHTONGE-0pt8THQcmcLdTbQAemacaRrGDFRF8PoH4THF-6R5pLqlJfk2WTnjK-O6zm5_XT98-pLc_P989ery5vGyZaVpkcOUydl7yzXA-_tyLVC6O3AheWSjapFiczqDgVjoCbsWa8160BK4NKJc_LxkLtfhwXH-qWS7Gz2yS82_THRevOYBH9ntvHecGhF16ka8P4YkOKvFXMxi88O59kGjGuunhZcc1HF5iC6FHNOOJ2GMDAP_Zjajzn1U_23_7_sn30spApvDsIul5hOXDLFa3kVvzvgyUZjt8lnc_uDAxPAQHeSa_EXJvGfQQ</recordid><startdate>20060605</startdate><enddate>20060605</enddate><creator>Woodward, Anna M</creator><creator>Göhler, Thomas</creator><creator>Luciani, M. 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Julian</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Excess Mcm2-7 license dormant origins of replication that can be used under conditions of replicative stress</atitle><jtitle>The Journal of cell biology</jtitle><addtitle>J Cell Biol</addtitle><date>2006-06-05</date><risdate>2006</risdate><volume>173</volume><issue>5</issue><spage>673</spage><epage>683</epage><pages>673-683</pages><issn>0021-9525</issn><eissn>1540-8140</eissn><abstract>In late mitosis and early G1, replication origins are licensed for subsequent use by loading complexes of the minichromosome maintenance proteins 2-7 (Mcm2-7). The number of Mcm2-7 complexes loaded onto DNA greatly exceeds the number of replication origins used during S phase, but the function of the excess Mcm2-7 is unknown. Using Xenopus laevis egg extracts, we show that these excess Mcm2-7 complexes license additional dormant origins that do not fire during unperturbed S phases because of suppression by a caffeine-sensitive checkpoint pathway. Use of these additional origins can allow complete genome replication in the presence of replication inhibitors. These results suggest that metazoan replication origins are actually comprised of several candidate origins, most of which normally remain dormant unless cells experience replicative stress. Consistent with this model, using Caenorhabditis elegans, we show that partial RNAi-based knockdown of MCMs that has no observable effect under normal conditions causes lethality upon treatment with low, otherwise nontoxic, levels of the replication inhibitor hydroxyurea.</abstract><cop>United States</cop><pub>The Rockefeller University Press</pub><pmid>16754955</pmid><doi>10.1083/jcb.200602108</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adenosine Triphosphatases - drug effects Adenosine Triphosphatases - metabolism Animals Aphidicolin - pharmacology Caenorhabditis elegans Caenorhabditis elegans - drug effects Caenorhabditis elegans - growth & development Caffeine - pharmacology Carrier Proteins - drug effects Carrier Proteins - metabolism Cell Cycle Proteins - drug effects Cell Cycle Proteins - metabolism Cell Survival - drug effects Chromatin Chromatin - drug effects Chromatin - metabolism DNA DNA replication DNA Replication - drug effects DNA Replication - physiology DNA-Binding Proteins - drug effects DNA-Binding Proteins - metabolism Gels Hydroxyurea - pharmacology Interphase Metazoa Minichromosome Maintenance Complex Component 2 Minichromosome Maintenance Complex Component 3 Minichromosome Maintenance Complex Component 4 Minichromosome Maintenance Complex Component 7 Molecules Nuclear Proteins - drug effects Nuclear Proteins - metabolism Ova Oxidative Stress - physiology Replication Origin Small interfering RNA Spermatozoa Time Factors Xenopus laevis Xenopus Proteins - drug effects Xenopus Proteins - metabolism |
| title | Excess Mcm2-7 license dormant origins of replication that can be used under conditions of replicative stress |
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