Mouse Ribonucleotide Reductase R2 Protein: A New Target for Anaphase-Promoting Complex-Cdh1-Mediated Proteolysis
Ribonucleotide reductase consists of two nonidentical proteins, R1 and R2, and catalyzes the rate-limiting step in DNA precursor synthesis: the reduction of ribonucleotides to deoxyribonucleotides. A strictly balanced supply of deoxyribonucleotides is essential for both accurate DNA replication and...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2003-04, Vol.100 (7), p.3925-3929 |
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| creator | Chabes, Anna Lena Pfleger, Cathie M. Kirschner, Marc W. Thelander, Lars |
| description | Ribonucleotide reductase consists of two nonidentical proteins, R1 and R2, and catalyzes the rate-limiting step in DNA precursor synthesis: the reduction of ribonucleotides to deoxyribonucleotides. A strictly balanced supply of deoxyribonucleotides is essential for both accurate DNA replication and repair. Therefore, ribonucleotide reductase activity is under exquisite control both transcriptionally and posttranscriptionally. In proliferating mammalian cells, enzyme activity is regulated by control of R2 protein stability. This control, which responds to DNA damage, is effective until cells pass into mitosis. We demonstrate that the mitotic degradation and hence the overall periodicity of R2 protein levels depends on a KEN box sequence, recognized by the Cdh1-anaphase-promoting complex. The mouse R2 protein specifically binds Cdh1 and is polyubiquitinated in an in vitro ubiquitin assay system. Mutating the KEN signal stabilizes the R2 protein during mitosis/G1 in R2 protein-overexpressing cells. The degradation process, which blocks deoxyribonucleotide production during G1, may be an important mechanism protecting the cell against unscheduled DNA synthesis. The newly discovered p53-induced p53R2 protein that lacks a KEN box may supply deoxyribonucleotides for DNA repair during G0/G1. |
| doi_str_mv | 10.1073/pnas.0330774100 |
| format | Article |
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A strictly balanced supply of deoxyribonucleotides is essential for both accurate DNA replication and repair. Therefore, ribonucleotide reductase activity is under exquisite control both transcriptionally and posttranscriptionally. In proliferating mammalian cells, enzyme activity is regulated by control of R2 protein stability. This control, which responds to DNA damage, is effective until cells pass into mitosis. We demonstrate that the mitotic degradation and hence the overall periodicity of R2 protein levels depends on a KEN box sequence, recognized by the Cdh1-anaphase-promoting complex. The mouse R2 protein specifically binds Cdh1 and is polyubiquitinated in an in vitro ubiquitin assay system. Mutating the KEN signal stabilizes the R2 protein during mitosis/G1 in R2 protein-overexpressing cells. The degradation process, which blocks deoxyribonucleotide production during G1, may be an important mechanism protecting the cell against unscheduled DNA synthesis. The newly discovered p53-induced p53R2 protein that lacks a KEN box may supply deoxyribonucleotides for DNA repair during G0/G1.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0330774100</identifier><identifier>PMID: 12655059</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>3T3 Cells ; Amino Acid Sequence ; Anaphase - physiology ; Anaphase-Promoting Complex-Cyclosome ; Animals ; Apoptosis - physiology ; Biological Sciences ; Cell cycle ; Cells ; Conserved Sequence ; Cricetinae ; Cytometry ; DNA damage ; Guinea Pigs ; Humans ; Immunoblotting ; Interphase ; Ligases - metabolism ; Mice ; Mitosis ; Molecular Sequence Data ; Oxidation-Reduction ; Proteins ; Recombinant Proteins - chemistry ; Recombinant Proteins - metabolism ; Ribonucleic acid ; Ribonucleotide Reductases - chemistry ; Ribonucleotide Reductases - genetics ; Ribonucleotide Reductases - metabolism ; Ribonucleotides ; RNA ; Rodents ; Sequence Alignment ; Sequence Homology, Amino Acid ; Starvation ; Substrate Specificity ; Transfection ; Ubiquitin - metabolism ; Ubiquitin-Protein Ligase Complexes</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2003-04, Vol.100 (7), p.3925-3929</ispartof><rights>Copyright 1993-2003 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Apr 1, 2003</rights><rights>Copyright © 2003, The National Academy of Sciences 2003</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c588t-83ffe7fe66128e2bb95db7d57e6c29fab94b91adad8d5cee8973ec53b4d833e53</citedby><cites>FETCH-LOGICAL-c588t-83ffe7fe66128e2bb95db7d57e6c29fab94b91adad8d5cee8973ec53b4d833e53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/100/7.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3148716$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3148716$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,724,777,781,800,882,27905,27906,53772,53774,57998,58231</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12655059$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chabes, Anna Lena</creatorcontrib><creatorcontrib>Pfleger, Cathie M.</creatorcontrib><creatorcontrib>Kirschner, Marc W.</creatorcontrib><creatorcontrib>Thelander, Lars</creatorcontrib><title>Mouse Ribonucleotide Reductase R2 Protein: A New Target for Anaphase-Promoting Complex-Cdh1-Mediated Proteolysis</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Ribonucleotide reductase consists of two nonidentical proteins, R1 and R2, and catalyzes the rate-limiting step in DNA precursor synthesis: the reduction of ribonucleotides to deoxyribonucleotides. A strictly balanced supply of deoxyribonucleotides is essential for both accurate DNA replication and repair. Therefore, ribonucleotide reductase activity is under exquisite control both transcriptionally and posttranscriptionally. In proliferating mammalian cells, enzyme activity is regulated by control of R2 protein stability. This control, which responds to DNA damage, is effective until cells pass into mitosis. We demonstrate that the mitotic degradation and hence the overall periodicity of R2 protein levels depends on a KEN box sequence, recognized by the Cdh1-anaphase-promoting complex. The mouse R2 protein specifically binds Cdh1 and is polyubiquitinated in an in vitro ubiquitin assay system. Mutating the KEN signal stabilizes the R2 protein during mitosis/G1 in R2 protein-overexpressing cells. The degradation process, which blocks deoxyribonucleotide production during G1, may be an important mechanism protecting the cell against unscheduled DNA synthesis. The newly discovered p53-induced p53R2 protein that lacks a KEN box may supply deoxyribonucleotides for DNA repair during G0/G1.</description><subject>3T3 Cells</subject><subject>Amino Acid Sequence</subject><subject>Anaphase - physiology</subject><subject>Anaphase-Promoting Complex-Cyclosome</subject><subject>Animals</subject><subject>Apoptosis - physiology</subject><subject>Biological Sciences</subject><subject>Cell cycle</subject><subject>Cells</subject><subject>Conserved Sequence</subject><subject>Cricetinae</subject><subject>Cytometry</subject><subject>DNA damage</subject><subject>Guinea Pigs</subject><subject>Humans</subject><subject>Immunoblotting</subject><subject>Interphase</subject><subject>Ligases - metabolism</subject><subject>Mice</subject><subject>Mitosis</subject><subject>Molecular Sequence Data</subject><subject>Oxidation-Reduction</subject><subject>Proteins</subject><subject>Recombinant Proteins - chemistry</subject><subject>Recombinant Proteins - metabolism</subject><subject>Ribonucleic acid</subject><subject>Ribonucleotide Reductases - chemistry</subject><subject>Ribonucleotide Reductases - genetics</subject><subject>Ribonucleotide Reductases - metabolism</subject><subject>Ribonucleotides</subject><subject>RNA</subject><subject>Rodents</subject><subject>Sequence Alignment</subject><subject>Sequence Homology, Amino Acid</subject><subject>Starvation</subject><subject>Substrate Specificity</subject><subject>Transfection</subject><subject>Ubiquitin - metabolism</subject><subject>Ubiquitin-Protein Ligase Complexes</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1v1DAQxSMEokvhzAWhiAOc0o7tOLaROKxWfEktIFTOlhNPdrPKxqntQPvf42hX3YKQOI2s-b0343lZ9pzAGQHBzsfBhDNgDIQoCcCDbEFAkaIqFTzMFgBUFLKk5Un2JIQtACgu4XF2QmjFOXC1yMZLNwXMv3e1G6amRxc7m55opyaauUHzb95F7Ia3-TL_gr_yK-PXGPPW-Xw5mHGTqCIhu6Qc1vnK7cYeb4qV3ZDiEm1nItq9hetvQxeeZo9a0wd8dqin2Y8P769Wn4qLrx8_r5YXRcOljIVkbYuixaoiVCKta8VtLSwXWDVUtaZWZa2IscZKyxtEqQTDhrO6tJIx5Ow0e7f3Had6h7bBIXrT69F3O-NvtTOd_rMzdBu9dj814QxomfSvD3rvricMUe-60GDfmwHTybRgpOKMiv-CRAqQwFkCX_0Fbt3kh3QETYGwUrFqHnu-hxrvQvDY3m1MQM-R6zlyfYw8KV7e_-iRP2ScgDcHYFYe7UALzRTlup36PuJNvGf1bzIBL_bANkTn7whGSilIxX4DUWTKpQ</recordid><startdate>20030401</startdate><enddate>20030401</enddate><creator>Chabes, Anna Lena</creator><creator>Pfleger, Cathie M.</creator><creator>Kirschner, Marc W.</creator><creator>Thelander, Lars</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><general>The National Academy of Sciences</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20030401</creationdate><title>Mouse Ribonucleotide Reductase R2 Protein: A New Target for Anaphase-Promoting Complex-Cdh1-Mediated Proteolysis</title><author>Chabes, Anna Lena ; 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A strictly balanced supply of deoxyribonucleotides is essential for both accurate DNA replication and repair. Therefore, ribonucleotide reductase activity is under exquisite control both transcriptionally and posttranscriptionally. In proliferating mammalian cells, enzyme activity is regulated by control of R2 protein stability. This control, which responds to DNA damage, is effective until cells pass into mitosis. We demonstrate that the mitotic degradation and hence the overall periodicity of R2 protein levels depends on a KEN box sequence, recognized by the Cdh1-anaphase-promoting complex. The mouse R2 protein specifically binds Cdh1 and is polyubiquitinated in an in vitro ubiquitin assay system. Mutating the KEN signal stabilizes the R2 protein during mitosis/G1 in R2 protein-overexpressing cells. The degradation process, which blocks deoxyribonucleotide production during G1, may be an important mechanism protecting the cell against unscheduled DNA synthesis. The newly discovered p53-induced p53R2 protein that lacks a KEN box may supply deoxyribonucleotides for DNA repair during G0/G1.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>12655059</pmid><doi>10.1073/pnas.0330774100</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 3T3 Cells Amino Acid Sequence Anaphase - physiology Anaphase-Promoting Complex-Cyclosome Animals Apoptosis - physiology Biological Sciences Cell cycle Cells Conserved Sequence Cricetinae Cytometry DNA damage Guinea Pigs Humans Immunoblotting Interphase Ligases - metabolism Mice Mitosis Molecular Sequence Data Oxidation-Reduction Proteins Recombinant Proteins - chemistry Recombinant Proteins - metabolism Ribonucleic acid Ribonucleotide Reductases - chemistry Ribonucleotide Reductases - genetics Ribonucleotide Reductases - metabolism Ribonucleotides RNA Rodents Sequence Alignment Sequence Homology, Amino Acid Starvation Substrate Specificity Transfection Ubiquitin - metabolism Ubiquitin-Protein Ligase Complexes |
| title | Mouse Ribonucleotide Reductase R2 Protein: A New Target for Anaphase-Promoting Complex-Cdh1-Mediated Proteolysis |
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