The RNA Exosome Targets the AID Cytidine Deaminase to Both Strands of Transcribed Duplex DNA Substrates
Activation-induced cytidine deaminase (AID) initiates immunoglobulin (Ig) heavy-chain (IgH) class switch recombination (CSR) and Ig variable region somatic hypermutation (SHM) in B lymphocytes by deaminating cytidines on template and nontemplate strands of transcribed DNA substrates. However, the me...
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| Veröffentlicht in: | Cell 2011-02, Vol.144 (3), p.353-363 |
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| creator | Basu, Uttiya Meng, Fei-Long Keim, Celia Grinstein, Veronika Pefanis, Evangelos Eccleston, Jennifer Zhang, Tingting Myers, Darienne Wasserman, Caitlyn R. Wesemann, Duane R. Januszyk, Kurt Gregory, Richard I. Deng, Haiteng Lima, Christopher D. Alt, Frederick W. |
| description | Activation-induced cytidine deaminase (AID) initiates immunoglobulin (Ig) heavy-chain (IgH) class switch recombination (CSR) and Ig variable region somatic hypermutation (SHM) in B lymphocytes by deaminating cytidines on template and nontemplate strands of transcribed DNA substrates. However, the mechanism of AID access to the template DNA strand, particularly when hybridized to a nascent RNA transcript, has been an enigma. We now implicate the RNA exosome, a cellular RNA-processing/degradation complex, in targeting AID to both DNA strands. In B lineage cells activated for CSR, the RNA exosome associates with AID, accumulates on IgH switch regions in an AID-dependent fashion, and is required for optimal CSR. Moreover, both the cellular RNA exosome complex and a recombinant RNA exosome core complex impart robust AID- and transcription-dependent DNA deamination of both strands of transcribed SHM substrates in vitro. Our findings reveal a role for noncoding RNA surveillance machinery in generating antibody diversity.
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► The RNA exosome, an RNA-processing/degradation machine, is required for IgH CSR ► AID recruits the RNA exosome to transcribed IgH switch regions ► The RNA exosome promotes AID activity on both strands of transcribed substrates |
| doi_str_mv | 10.1016/j.cell.2011.01.001 |
| format | Article |
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[Display omitted]
► The RNA exosome, an RNA-processing/degradation machine, is required for IgH CSR ► AID recruits the RNA exosome to transcribed IgH switch regions ► The RNA exosome promotes AID activity on both strands of transcribed substrates</description><identifier>ISSN: 0092-8674</identifier><identifier>EISSN: 1097-4172</identifier><identifier>DOI: 10.1016/j.cell.2011.01.001</identifier><identifier>PMID: 21255825</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; antibody diversity ; B-lymphocytes ; B-Lymphocytes - cytology ; B-Lymphocytes - enzymology ; B-Lymphocytes - metabolism ; Cell Line ; Cells, Cultured ; cytidine deaminase ; Cytidine Deaminase - metabolism ; cytology ; deamination ; DNA ; enzymology ; Exoribonucleases ; Exoribonucleases - metabolism ; genetics ; Humans ; Immunoglobulin Class Switching ; Immunoglobulin Heavy Chains ; Immunoglobulin Heavy Chains - genetics ; immunoglobulins ; messenger RNA ; metabolism ; Mice ; Multienzyme Complexes ; Multienzyme Complexes - metabolism ; non-coding RNA ; RNA ; RNA - metabolism ; transcription (genetics) ; Transcription, Genetic</subject><ispartof>Cell, 2011-02, Vol.144 (3), p.353-363</ispartof><rights>2011 Elsevier Inc.</rights><rights>Copyright © 2011 Elsevier Inc. All rights reserved.</rights><rights>2011 Elsevier Inc. All rights reserved. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c585t-b8dbfc9dd1f3d52ce287460f12cf0d78e5d117f6337c36647fed79c880f6fbc33</citedby><cites>FETCH-LOGICAL-c585t-b8dbfc9dd1f3d52ce287460f12cf0d78e5d117f6337c36647fed79c880f6fbc33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S009286741100002X$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21255825$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Basu, Uttiya</creatorcontrib><creatorcontrib>Meng, Fei-Long</creatorcontrib><creatorcontrib>Keim, Celia</creatorcontrib><creatorcontrib>Grinstein, Veronika</creatorcontrib><creatorcontrib>Pefanis, Evangelos</creatorcontrib><creatorcontrib>Eccleston, Jennifer</creatorcontrib><creatorcontrib>Zhang, Tingting</creatorcontrib><creatorcontrib>Myers, Darienne</creatorcontrib><creatorcontrib>Wasserman, Caitlyn R.</creatorcontrib><creatorcontrib>Wesemann, Duane R.</creatorcontrib><creatorcontrib>Januszyk, Kurt</creatorcontrib><creatorcontrib>Gregory, Richard I.</creatorcontrib><creatorcontrib>Deng, Haiteng</creatorcontrib><creatorcontrib>Lima, Christopher D.</creatorcontrib><creatorcontrib>Alt, Frederick W.</creatorcontrib><title>The RNA Exosome Targets the AID Cytidine Deaminase to Both Strands of Transcribed Duplex DNA Substrates</title><title>Cell</title><addtitle>Cell</addtitle><description>Activation-induced cytidine deaminase (AID) initiates immunoglobulin (Ig) heavy-chain (IgH) class switch recombination (CSR) and Ig variable region somatic hypermutation (SHM) in B lymphocytes by deaminating cytidines on template and nontemplate strands of transcribed DNA substrates. However, the mechanism of AID access to the template DNA strand, particularly when hybridized to a nascent RNA transcript, has been an enigma. We now implicate the RNA exosome, a cellular RNA-processing/degradation complex, in targeting AID to both DNA strands. In B lineage cells activated for CSR, the RNA exosome associates with AID, accumulates on IgH switch regions in an AID-dependent fashion, and is required for optimal CSR. Moreover, both the cellular RNA exosome complex and a recombinant RNA exosome core complex impart robust AID- and transcription-dependent DNA deamination of both strands of transcribed SHM substrates in vitro. Our findings reveal a role for noncoding RNA surveillance machinery in generating antibody diversity.
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► The RNA exosome, an RNA-processing/degradation machine, is required for IgH CSR ► AID recruits the RNA exosome to transcribed IgH switch regions ► The RNA exosome promotes AID activity on both strands of transcribed substrates</description><subject>Animals</subject><subject>antibody diversity</subject><subject>B-lymphocytes</subject><subject>B-Lymphocytes - cytology</subject><subject>B-Lymphocytes - enzymology</subject><subject>B-Lymphocytes - metabolism</subject><subject>Cell Line</subject><subject>Cells, Cultured</subject><subject>cytidine deaminase</subject><subject>Cytidine Deaminase - metabolism</subject><subject>cytology</subject><subject>deamination</subject><subject>DNA</subject><subject>enzymology</subject><subject>Exoribonucleases</subject><subject>Exoribonucleases - metabolism</subject><subject>genetics</subject><subject>Humans</subject><subject>Immunoglobulin Class Switching</subject><subject>Immunoglobulin Heavy Chains</subject><subject>Immunoglobulin Heavy Chains - genetics</subject><subject>immunoglobulins</subject><subject>messenger RNA</subject><subject>metabolism</subject><subject>Mice</subject><subject>Multienzyme Complexes</subject><subject>Multienzyme Complexes - metabolism</subject><subject>non-coding RNA</subject><subject>RNA</subject><subject>RNA - metabolism</subject><subject>transcription (genetics)</subject><subject>Transcription, Genetic</subject><issn>0092-8674</issn><issn>1097-4172</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkV-LEzEUxQdR3Lr6BXyQvOnL1JvM5M-ACLVddWFRcOtzmElu2pTppCYzy-63N6Xroi8rXEhIfufk5p6ieE1hToGK97u5wb6fM6B0DrmAPilmFBpZ1lSyp8UMoGGlErI-K16ktAMAxTl_XpwxyjhXjM-KzXqL5Me3Bbm4DSnskazbuMExkTGfLy5XZHk3eusHJCts935oE5IxkE9h3JLrMbaDTSQ4ss67ZKLv0JLVdOjxlqyy6fXUpQyNmF4Wz1zbJ3x1v54XPz9frJdfy6vvXy6Xi6vScMXHslO2c6axlrrKcmaQKVkLcJQZB1Yq5JZS6URVSVMJUUuHVjZGKXDCdaaqzouPJ9_D1O3RGhzy-70-RL9v450Ordf_3gx-qzfhRlcgOKV1Nnh7bxDDrwnTqPc-HefcDhimpHM_VIGg8v8kB86bholMvnuUpEIyUFXNWUbZCTUxpBTRPbROQR9T1zt9VOpj6hpyAc2iN39_-kHyJ-YMfDgBmEd_4zHqZDwOBq2PaEZtg3_M_zezRr4I</recordid><startdate>20110204</startdate><enddate>20110204</enddate><creator>Basu, Uttiya</creator><creator>Meng, Fei-Long</creator><creator>Keim, Celia</creator><creator>Grinstein, Veronika</creator><creator>Pefanis, Evangelos</creator><creator>Eccleston, Jennifer</creator><creator>Zhang, Tingting</creator><creator>Myers, Darienne</creator><creator>Wasserman, Caitlyn R.</creator><creator>Wesemann, Duane R.</creator><creator>Januszyk, Kurt</creator><creator>Gregory, Richard I.</creator><creator>Deng, Haiteng</creator><creator>Lima, Christopher D.</creator><creator>Alt, Frederick 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>7S9</scope><scope>L.6</scope><scope>7X8</scope><scope>7TM</scope><scope>5PM</scope></search><sort><creationdate>20110204</creationdate><title>The RNA Exosome Targets the AID Cytidine Deaminase to Both Strands of Transcribed Duplex DNA Substrates</title><author>Basu, Uttiya ; Meng, Fei-Long ; Keim, Celia ; Grinstein, Veronika ; Pefanis, Evangelos ; Eccleston, Jennifer ; Zhang, Tingting ; Myers, Darienne ; Wasserman, Caitlyn R. ; Wesemann, Duane R. ; Januszyk, Kurt ; Gregory, Richard I. ; Deng, Haiteng ; Lima, Christopher D. ; Alt, Frederick W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c585t-b8dbfc9dd1f3d52ce287460f12cf0d78e5d117f6337c36647fed79c880f6fbc33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Animals</topic><topic>antibody diversity</topic><topic>B-lymphocytes</topic><topic>B-Lymphocytes - cytology</topic><topic>B-Lymphocytes - enzymology</topic><topic>B-Lymphocytes - metabolism</topic><topic>Cell Line</topic><topic>Cells, Cultured</topic><topic>cytidine deaminase</topic><topic>Cytidine Deaminase - metabolism</topic><topic>cytology</topic><topic>deamination</topic><topic>DNA</topic><topic>enzymology</topic><topic>Exoribonucleases</topic><topic>Exoribonucleases - metabolism</topic><topic>genetics</topic><topic>Humans</topic><topic>Immunoglobulin Class Switching</topic><topic>Immunoglobulin Heavy Chains</topic><topic>Immunoglobulin Heavy Chains - genetics</topic><topic>immunoglobulins</topic><topic>messenger RNA</topic><topic>metabolism</topic><topic>Mice</topic><topic>Multienzyme Complexes</topic><topic>Multienzyme Complexes - metabolism</topic><topic>non-coding RNA</topic><topic>RNA</topic><topic>RNA - metabolism</topic><topic>transcription (genetics)</topic><topic>Transcription, Genetic</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Basu, Uttiya</creatorcontrib><creatorcontrib>Meng, Fei-Long</creatorcontrib><creatorcontrib>Keim, Celia</creatorcontrib><creatorcontrib>Grinstein, Veronika</creatorcontrib><creatorcontrib>Pefanis, Evangelos</creatorcontrib><creatorcontrib>Eccleston, Jennifer</creatorcontrib><creatorcontrib>Zhang, Tingting</creatorcontrib><creatorcontrib>Myers, Darienne</creatorcontrib><creatorcontrib>Wasserman, Caitlyn R.</creatorcontrib><creatorcontrib>Wesemann, Duane R.</creatorcontrib><creatorcontrib>Januszyk, Kurt</creatorcontrib><creatorcontrib>Gregory, Richard I.</creatorcontrib><creatorcontrib>Deng, Haiteng</creatorcontrib><creatorcontrib>Lima, Christopher D.</creatorcontrib><creatorcontrib>Alt, Frederick 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>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><collection>MEDLINE - Academic</collection><collection>Nucleic Acids Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Basu, Uttiya</au><au>Meng, Fei-Long</au><au>Keim, Celia</au><au>Grinstein, Veronika</au><au>Pefanis, Evangelos</au><au>Eccleston, Jennifer</au><au>Zhang, Tingting</au><au>Myers, Darienne</au><au>Wasserman, Caitlyn R.</au><au>Wesemann, Duane R.</au><au>Januszyk, Kurt</au><au>Gregory, Richard I.</au><au>Deng, Haiteng</au><au>Lima, Christopher D.</au><au>Alt, Frederick W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The RNA Exosome Targets the AID Cytidine Deaminase to Both Strands of Transcribed Duplex DNA Substrates</atitle><jtitle>Cell</jtitle><addtitle>Cell</addtitle><date>2011-02-04</date><risdate>2011</risdate><volume>144</volume><issue>3</issue><spage>353</spage><epage>363</epage><pages>353-363</pages><issn>0092-8674</issn><eissn>1097-4172</eissn><abstract>Activation-induced cytidine deaminase (AID) initiates immunoglobulin (Ig) heavy-chain (IgH) class switch recombination (CSR) and Ig variable region somatic hypermutation (SHM) in B lymphocytes by deaminating cytidines on template and nontemplate strands of transcribed DNA substrates. However, the mechanism of AID access to the template DNA strand, particularly when hybridized to a nascent RNA transcript, has been an enigma. We now implicate the RNA exosome, a cellular RNA-processing/degradation complex, in targeting AID to both DNA strands. In B lineage cells activated for CSR, the RNA exosome associates with AID, accumulates on IgH switch regions in an AID-dependent fashion, and is required for optimal CSR. Moreover, both the cellular RNA exosome complex and a recombinant RNA exosome core complex impart robust AID- and transcription-dependent DNA deamination of both strands of transcribed SHM substrates in vitro. Our findings reveal a role for noncoding RNA surveillance machinery in generating antibody diversity.
[Display omitted]
► The RNA exosome, an RNA-processing/degradation machine, is required for IgH CSR ► AID recruits the RNA exosome to transcribed IgH switch regions ► The RNA exosome promotes AID activity on both strands of transcribed substrates</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>21255825</pmid><doi>10.1016/j.cell.2011.01.001</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals antibody diversity B-lymphocytes B-Lymphocytes - cytology B-Lymphocytes - enzymology B-Lymphocytes - metabolism Cell Line Cells, Cultured cytidine deaminase Cytidine Deaminase - metabolism cytology deamination DNA enzymology Exoribonucleases Exoribonucleases - metabolism genetics Humans Immunoglobulin Class Switching Immunoglobulin Heavy Chains Immunoglobulin Heavy Chains - genetics immunoglobulins messenger RNA metabolism Mice Multienzyme Complexes Multienzyme Complexes - metabolism non-coding RNA RNA RNA - metabolism transcription (genetics) Transcription, Genetic |
| title | The RNA Exosome Targets the AID Cytidine Deaminase to Both Strands of Transcribed Duplex DNA Substrates |
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