ATR Regulates Fragile Site Stability
Conditions that partially inhibit DNA replication induce expression of common fragile sites. These sites form gaps and breaks on metaphase chromosomes and are deleted and rearranged in many tumors. Yet, the mechanism of fragile site expression has been elusive. We demonstrate that the replication ch...
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| Veröffentlicht in: | Cell 2002-12, Vol.111 (6), p.779-789 |
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| container_title | Cell |
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| creator | Casper, Anne M. Nghiem, Paul Arlt, Martin F. Glover, Thomas W. |
| description | Conditions that partially inhibit DNA replication induce expression of common fragile sites. These sites form gaps and breaks on metaphase chromosomes and are deleted and rearranged in many tumors. Yet, the mechanism of fragile site expression has been elusive. We demonstrate that the replication checkpoint kinase ATR, but not ATM, is critical for maintenance of fragile site stability. ATR deficiency results in fragile site expression with and without addition of replication inhibitors. Thus, we propose that fragile sites are unreplicated chromosomal regions resulting from stalled forks that escape the ATR replication checkpoint. These findings have important implications for understanding both the mechanism of fragile site instability and the consequences of stalled replication in mammalian cells. |
| doi_str_mv | 10.1016/S0092-8674(02)01113-3 |
| format | Article |
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These sites form gaps and breaks on metaphase chromosomes and are deleted and rearranged in many tumors. Yet, the mechanism of fragile site expression has been elusive. We demonstrate that the replication checkpoint kinase ATR, but not ATM, is critical for maintenance of fragile site stability. ATR deficiency results in fragile site expression with and without addition of replication inhibitors. Thus, we propose that fragile sites are unreplicated chromosomal regions resulting from stalled forks that escape the ATR replication checkpoint. These findings have important implications for understanding both the mechanism of fragile site instability and the consequences of stalled replication in mammalian cells.</description><identifier>ISSN: 0092-8674</identifier><identifier>EISSN: 1097-4172</identifier><identifier>DOI: 10.1016/S0092-8674(02)01113-3</identifier><identifier>PMID: 12526805</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>2-Aminopurine - pharmacology ; Antimetabolites - pharmacology ; Aphidicolin - pharmacology ; Ataxia Telangiectasia Mutated Proteins ; Blotting, Western ; Caffeine - pharmacology ; Cell Cycle Proteins - physiology ; Cells, Cultured ; Chromosome Fragile Sites ; Chromosome Fragility ; Chromosomes - drug effects ; DNA - biosynthesis ; DNA-Binding Proteins ; Dose-Response Relationship, Drug ; HeLa Cells ; Humans ; Metaphase ; Microscopy, Fluorescence ; Models, Biological ; Phosphodiesterase Inhibitors - pharmacology ; Protein-Serine-Threonine Kinases - metabolism ; Tumor Suppressor Proteins</subject><ispartof>Cell, 2002-12, Vol.111 (6), p.779-789</ispartof><rights>2002 Cell Press</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c491t-729af4ebaea0dd76f881f94aacd552c791a06b325c9be10cbb75bf36e779a2fc3</citedby><cites>FETCH-LOGICAL-c491t-729af4ebaea0dd76f881f94aacd552c791a06b325c9be10cbb75bf36e779a2fc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/S0092-8674(02)01113-3$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12526805$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Casper, Anne M.</creatorcontrib><creatorcontrib>Nghiem, Paul</creatorcontrib><creatorcontrib>Arlt, Martin F.</creatorcontrib><creatorcontrib>Glover, Thomas W.</creatorcontrib><title>ATR Regulates Fragile Site Stability</title><title>Cell</title><addtitle>Cell</addtitle><description>Conditions that partially inhibit DNA replication induce expression of common fragile sites. These sites form gaps and breaks on metaphase chromosomes and are deleted and rearranged in many tumors. Yet, the mechanism of fragile site expression has been elusive. We demonstrate that the replication checkpoint kinase ATR, but not ATM, is critical for maintenance of fragile site stability. ATR deficiency results in fragile site expression with and without addition of replication inhibitors. Thus, we propose that fragile sites are unreplicated chromosomal regions resulting from stalled forks that escape the ATR replication checkpoint. These findings have important implications for understanding both the mechanism of fragile site instability and the consequences of stalled replication in mammalian cells.</description><subject>2-Aminopurine - pharmacology</subject><subject>Antimetabolites - pharmacology</subject><subject>Aphidicolin - pharmacology</subject><subject>Ataxia Telangiectasia Mutated Proteins</subject><subject>Blotting, Western</subject><subject>Caffeine - pharmacology</subject><subject>Cell Cycle Proteins - physiology</subject><subject>Cells, Cultured</subject><subject>Chromosome Fragile Sites</subject><subject>Chromosome Fragility</subject><subject>Chromosomes - drug effects</subject><subject>DNA - biosynthesis</subject><subject>DNA-Binding Proteins</subject><subject>Dose-Response Relationship, Drug</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Metaphase</subject><subject>Microscopy, Fluorescence</subject><subject>Models, Biological</subject><subject>Phosphodiesterase Inhibitors - pharmacology</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Tumor Suppressor Proteins</subject><issn>0092-8674</issn><issn>1097-4172</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkE1LAzEQhoMotn78BKUHET2sTrKbZHOSUqwKBaGt55BkZ0tk263JrtB_7_YDPXqZuTzvvMxDyBWFBwpUPM4AFEtyIbM7YPdAKU2T9Ij0KSiZZFSyY9L_RXrkLMZPAMg556ekRxlnIgfeJzfD-XQwxUVbmQbjYBzMwlc4mPmmG42xvvLN5oKclKaKeHnY5-Rj_DwfvSaT95e30XCSuEzRJpFMmTJDa9BAUUhR5jktVWaMKzhnTipqQNiUcacsUnDWSm7LVKCUyrDSpefkdn93HeqvFmOjlz46rCqzwrqNmuYiE3nGOpDvQRfqGAOWeh380oSNpqC3evROj97-roHpnR6ddrnrQ0Frl1j8pQ4-OuBpD2D35rfHoKPzuHJY-ICu0UXt_6n4ATqtc1Y</recordid><startdate>20021213</startdate><enddate>20021213</enddate><creator>Casper, Anne M.</creator><creator>Nghiem, Paul</creator><creator>Arlt, Martin F.</creator><creator>Glover, Thomas W.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</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>7TM</scope></search><sort><creationdate>20021213</creationdate><title>ATR Regulates Fragile Site Stability</title><author>Casper, Anne M. ; Nghiem, Paul ; Arlt, Martin F. ; Glover, Thomas W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c491t-729af4ebaea0dd76f881f94aacd552c791a06b325c9be10cbb75bf36e779a2fc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>2-Aminopurine - pharmacology</topic><topic>Antimetabolites - pharmacology</topic><topic>Aphidicolin - pharmacology</topic><topic>Ataxia Telangiectasia Mutated Proteins</topic><topic>Blotting, Western</topic><topic>Caffeine - pharmacology</topic><topic>Cell Cycle Proteins - physiology</topic><topic>Cells, Cultured</topic><topic>Chromosome Fragile Sites</topic><topic>Chromosome Fragility</topic><topic>Chromosomes - drug effects</topic><topic>DNA - biosynthesis</topic><topic>DNA-Binding Proteins</topic><topic>Dose-Response Relationship, Drug</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>Metaphase</topic><topic>Microscopy, Fluorescence</topic><topic>Models, Biological</topic><topic>Phosphodiesterase Inhibitors - pharmacology</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Tumor Suppressor Proteins</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Casper, Anne M.</creatorcontrib><creatorcontrib>Nghiem, Paul</creatorcontrib><creatorcontrib>Arlt, Martin F.</creatorcontrib><creatorcontrib>Glover, Thomas W.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><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><jtitle>Cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Casper, Anne M.</au><au>Nghiem, Paul</au><au>Arlt, Martin F.</au><au>Glover, Thomas W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>ATR Regulates Fragile Site Stability</atitle><jtitle>Cell</jtitle><addtitle>Cell</addtitle><date>2002-12-13</date><risdate>2002</risdate><volume>111</volume><issue>6</issue><spage>779</spage><epage>789</epage><pages>779-789</pages><issn>0092-8674</issn><eissn>1097-4172</eissn><abstract>Conditions that partially inhibit DNA replication induce expression of common fragile sites. These sites form gaps and breaks on metaphase chromosomes and are deleted and rearranged in many tumors. Yet, the mechanism of fragile site expression has been elusive. We demonstrate that the replication checkpoint kinase ATR, but not ATM, is critical for maintenance of fragile site stability. ATR deficiency results in fragile site expression with and without addition of replication inhibitors. Thus, we propose that fragile sites are unreplicated chromosomal regions resulting from stalled forks that escape the ATR replication checkpoint. These findings have important implications for understanding both the mechanism of fragile site instability and the consequences of stalled replication in mammalian cells.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>12526805</pmid><doi>10.1016/S0092-8674(02)01113-3</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Cell Press Free Archives; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Access via ScienceDirect (Elsevier) |
| subjects | 2-Aminopurine - pharmacology Antimetabolites - pharmacology Aphidicolin - pharmacology Ataxia Telangiectasia Mutated Proteins Blotting, Western Caffeine - pharmacology Cell Cycle Proteins - physiology Cells, Cultured Chromosome Fragile Sites Chromosome Fragility Chromosomes - drug effects DNA - biosynthesis DNA-Binding Proteins Dose-Response Relationship, Drug HeLa Cells Humans Metaphase Microscopy, Fluorescence Models, Biological Phosphodiesterase Inhibitors - pharmacology Protein-Serine-Threonine Kinases - metabolism Tumor Suppressor Proteins |
| title | ATR Regulates Fragile Site Stability |
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