Repair of U/G and U/A in DNA by UNG2-associated repair complexes takes place predominantly by short-patch repair both in proliferating and growth-arrested cells
Nuclear uracil-DNA glycosylase UNG2 has an established role in repair of U/A pairs resulting from misincorporation of dUMP during replication. In antigen-stimulated B-lymphocytes UNG2 removes uracil from U/G mispairs as part of somatic hypermutation and class switch recombination processes. Using an...
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| Veröffentlicht in: | Nucleic acids research 2004-01, Vol.32 (18), p.5486-5498 |
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| creator | Akbari, Mansour Otterlei, Marit Peña-Diaz, Javier Aas, Per Arne Kavli, Bodil Liabakk, Nina B. Hagen, Lars Imai, Kohsuke Durandy, Anne Slupphaug, Geir Krokan, Hans E. |
| description | Nuclear uracil-DNA glycosylase UNG2 has an established role in repair of U/A pairs resulting from misincorporation of dUMP during replication. In antigen-stimulated B-lymphocytes UNG2 removes uracil from U/G mispairs as part of somatic hypermutation and class switch recombination processes. Using antibodies specific for the N-terminal non-catalytic domain of UNG2, we isolated UNG2-associated repair complexes (UNG2-ARC) that carry out short-patch and long-patch base excision repair (BER). These complexes contain proteins required for both types of BER, including UNG2, APE1, POLβ, POLδ, XRCC1, PCNA and DNA ligase, the latter detected as activity. Short-patch repair was the predominant mechanism both in extracts and UNG2-ARC from proliferating and less BER-proficient growth-arrested cells. Repair of U/G mispairs and U/A pairs was completely inhibited by neutralizing UNG-antibodies, but whereas added recombinant SMUG1 could partially restore repair of U/G mispairs, it was unable to restore repair of U/A pairs in UNG2-ARC. Neutralizing antibodies to APE1 and POLβ, and depletion of XRCC1 strongly reduced short-patch BER, and a fraction of long-patch repair was POLβ dependent. In conclusion, UNG2 is present in preassembled complexes proficient in BER. Furthermore, UNG2 is the major enzyme initiating BER of deaminated cytosine (U/G), and possibly the sole enzyme initiating BER of misincorporated uracil (U/A). |
| doi_str_mv | 10.1093/nar/gkh872 |
| format | Article |
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In antigen-stimulated B-lymphocytes UNG2 removes uracil from U/G mispairs as part of somatic hypermutation and class switch recombination processes. Using antibodies specific for the N-terminal non-catalytic domain of UNG2, we isolated UNG2-associated repair complexes (UNG2-ARC) that carry out short-patch and long-patch base excision repair (BER). These complexes contain proteins required for both types of BER, including UNG2, APE1, POLβ, POLδ, XRCC1, PCNA and DNA ligase, the latter detected as activity. Short-patch repair was the predominant mechanism both in extracts and UNG2-ARC from proliferating and less BER-proficient growth-arrested cells. Repair of U/G mispairs and U/A pairs was completely inhibited by neutralizing UNG-antibodies, but whereas added recombinant SMUG1 could partially restore repair of U/G mispairs, it was unable to restore repair of U/A pairs in UNG2-ARC. Neutralizing antibodies to APE1 and POLβ, and depletion of XRCC1 strongly reduced short-patch BER, and a fraction of long-patch repair was POLβ dependent. In conclusion, UNG2 is present in preassembled complexes proficient in BER. Furthermore, UNG2 is the major enzyme initiating BER of deaminated cytosine (U/G), and possibly the sole enzyme initiating BER of misincorporated uracil (U/A).</description><identifier>ISSN: 0305-1048</identifier><identifier>ISSN: 1362-4962</identifier><identifier>EISSN: 1362-4962</identifier><identifier>DOI: 10.1093/nar/gkh872</identifier><identifier>PMID: 15479784</identifier><identifier>CODEN: NARHAD</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Cell Division ; Cell Line ; DNA - chemistry ; DNA - metabolism ; DNA Glycosylases - antagonists & inhibitors ; DNA Glycosylases - immunology ; DNA Glycosylases - metabolism ; DNA Repair ; DNA-(Apurinic or Apyrimidinic Site) Lyase - physiology ; DNA-Binding Proteins - antagonists & inhibitors ; HeLa Cells ; Humans ; Macromolecular Substances ; Precipitin Tests ; Substrate Specificity ; Uracil - metabolism ; Uracil-DNA Glycosidase ; X-ray Repair Cross Complementing Protein 1</subject><ispartof>Nucleic acids research, 2004-01, Vol.32 (18), p.5486-5498</ispartof><rights>Copyright Oxford University Press(England) 2004</rights><rights>Copyright © 2004 Oxford University Press 2004</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c566t-8b4fdfd2af3f4c7bab8b143586630420feedee0f4d51fbbb277153fa5f1df46d3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC524284/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC524284/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,315,728,781,785,886,27929,27930,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15479784$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Akbari, Mansour</creatorcontrib><creatorcontrib>Otterlei, Marit</creatorcontrib><creatorcontrib>Peña-Diaz, Javier</creatorcontrib><creatorcontrib>Aas, Per Arne</creatorcontrib><creatorcontrib>Kavli, Bodil</creatorcontrib><creatorcontrib>Liabakk, Nina B.</creatorcontrib><creatorcontrib>Hagen, Lars</creatorcontrib><creatorcontrib>Imai, Kohsuke</creatorcontrib><creatorcontrib>Durandy, Anne</creatorcontrib><creatorcontrib>Slupphaug, Geir</creatorcontrib><creatorcontrib>Krokan, Hans E.</creatorcontrib><title>Repair of U/G and U/A in DNA by UNG2-associated repair complexes takes place predominantly by short-patch repair both in proliferating and growth-arrested cells</title><title>Nucleic acids research</title><addtitle>Nucl. Acids Res</addtitle><description>Nuclear uracil-DNA glycosylase UNG2 has an established role in repair of U/A pairs resulting from misincorporation of dUMP during replication. In antigen-stimulated B-lymphocytes UNG2 removes uracil from U/G mispairs as part of somatic hypermutation and class switch recombination processes. Using antibodies specific for the N-terminal non-catalytic domain of UNG2, we isolated UNG2-associated repair complexes (UNG2-ARC) that carry out short-patch and long-patch base excision repair (BER). These complexes contain proteins required for both types of BER, including UNG2, APE1, POLβ, POLδ, XRCC1, PCNA and DNA ligase, the latter detected as activity. Short-patch repair was the predominant mechanism both in extracts and UNG2-ARC from proliferating and less BER-proficient growth-arrested cells. Repair of U/G mispairs and U/A pairs was completely inhibited by neutralizing UNG-antibodies, but whereas added recombinant SMUG1 could partially restore repair of U/G mispairs, it was unable to restore repair of U/A pairs in UNG2-ARC. Neutralizing antibodies to APE1 and POLβ, and depletion of XRCC1 strongly reduced short-patch BER, and a fraction of long-patch repair was POLβ dependent. In conclusion, UNG2 is present in preassembled complexes proficient in BER. Furthermore, UNG2 is the major enzyme initiating BER of deaminated cytosine (U/G), and possibly the sole enzyme initiating BER of misincorporated uracil (U/A).</description><subject>Cell Division</subject><subject>Cell Line</subject><subject>DNA - chemistry</subject><subject>DNA - metabolism</subject><subject>DNA Glycosylases - antagonists & inhibitors</subject><subject>DNA Glycosylases - immunology</subject><subject>DNA Glycosylases - metabolism</subject><subject>DNA Repair</subject><subject>DNA-(Apurinic or Apyrimidinic Site) Lyase - physiology</subject><subject>DNA-Binding Proteins - antagonists & inhibitors</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Macromolecular Substances</subject><subject>Precipitin Tests</subject><subject>Substrate Specificity</subject><subject>Uracil - metabolism</subject><subject>Uracil-DNA Glycosidase</subject><subject>X-ray Repair Cross Complementing Protein 1</subject><issn>0305-1048</issn><issn>1362-4962</issn><issn>1362-4962</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkk1v1DAQhi0EotvChR-ALA4cKoX1d5IDh1WBLVJVJGBFxcVyEnvjbjYOthe6_4afitMs5ePSy8xhnnnHM34BeIbRK4xKOu-Vn683bZGTB2CGqSAZKwV5CGaIIp5hxIojcBzCNUKYYc4eg6MU8zIv2Az8_KgHZT10Bq7mS6j6JuUFtD18c7mA1R6uLpckUyG42qqoG-gnvnbbodM3OsCoNikOnao1HLxu3Nb2qo_dfuwOrfMxG1Ss29-dlYvtqD9411mjvYq2X98OXnv3I7aZ8l6HcVStuy48AY-M6oJ-esgnYPXu7eez8-ziw_L92eIiq7kQMSsqZhrTEGWoYXVeqaqoMKO8EIIiRpDRutEaGdZwbKqqInmOOTWKG9wYJhp6Al5PusOu2uqm1n30qpODt1vl99IpK_-t9LaVa_ddcsJIwVL_y0O_d992aQG5tWHcQPXa7YIUohS0zMt7QYI4Yiw9-z4Ql0mzLEfwxX_gtdv5Pl0riSGBCbpVO52g2rsQvDZ3q2EkRxvJZCM52SjBz_8-xh_04JsEZBNg00_d3NWV30iR05zL86uvUlx9IZ8KziWjvwCBdtZ-</recordid><startdate>20040101</startdate><enddate>20040101</enddate><creator>Akbari, Mansour</creator><creator>Otterlei, Marit</creator><creator>Peña-Diaz, Javier</creator><creator>Aas, Per Arne</creator><creator>Kavli, Bodil</creator><creator>Liabakk, Nina B.</creator><creator>Hagen, Lars</creator><creator>Imai, Kohsuke</creator><creator>Durandy, Anne</creator><creator>Slupphaug, Geir</creator><creator>Krokan, Hans E.</creator><general>Oxford University Press</general><general>Oxford Publishing Limited (England)</general><scope>BSCLL</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>7QL</scope><scope>7QO</scope><scope>7QP</scope><scope>7QR</scope><scope>7SS</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20040101</creationdate><title>Repair of U/G and U/A in DNA by UNG2-associated repair complexes takes place predominantly by short-patch repair both in proliferating and growth-arrested cells</title><author>Akbari, Mansour ; 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Acids Res</addtitle><date>2004-01-01</date><risdate>2004</risdate><volume>32</volume><issue>18</issue><spage>5486</spage><epage>5498</epage><pages>5486-5498</pages><issn>0305-1048</issn><issn>1362-4962</issn><eissn>1362-4962</eissn><coden>NARHAD</coden><abstract>Nuclear uracil-DNA glycosylase UNG2 has an established role in repair of U/A pairs resulting from misincorporation of dUMP during replication. In antigen-stimulated B-lymphocytes UNG2 removes uracil from U/G mispairs as part of somatic hypermutation and class switch recombination processes. Using antibodies specific for the N-terminal non-catalytic domain of UNG2, we isolated UNG2-associated repair complexes (UNG2-ARC) that carry out short-patch and long-patch base excision repair (BER). These complexes contain proteins required for both types of BER, including UNG2, APE1, POLβ, POLδ, XRCC1, PCNA and DNA ligase, the latter detected as activity. Short-patch repair was the predominant mechanism both in extracts and UNG2-ARC from proliferating and less BER-proficient growth-arrested cells. Repair of U/G mispairs and U/A pairs was completely inhibited by neutralizing UNG-antibodies, but whereas added recombinant SMUG1 could partially restore repair of U/G mispairs, it was unable to restore repair of U/A pairs in UNG2-ARC. Neutralizing antibodies to APE1 and POLβ, and depletion of XRCC1 strongly reduced short-patch BER, and a fraction of long-patch repair was POLβ dependent. In conclusion, UNG2 is present in preassembled complexes proficient in BER. Furthermore, UNG2 is the major enzyme initiating BER of deaminated cytosine (U/G), and possibly the sole enzyme initiating BER of misincorporated uracil (U/A).</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>15479784</pmid><doi>10.1093/nar/gkh872</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Cell Division Cell Line DNA - chemistry DNA - metabolism DNA Glycosylases - antagonists & inhibitors DNA Glycosylases - immunology DNA Glycosylases - metabolism DNA Repair DNA-(Apurinic or Apyrimidinic Site) Lyase - physiology DNA-Binding Proteins - antagonists & inhibitors HeLa Cells Humans Macromolecular Substances Precipitin Tests Substrate Specificity Uracil - metabolism Uracil-DNA Glycosidase X-ray Repair Cross Complementing Protein 1 |
| title | Repair of U/G and U/A in DNA by UNG2-associated repair complexes takes place predominantly by short-patch repair both in proliferating and growth-arrested cells |
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