USP47 Is a Deubiquitylating Enzyme that Regulates Base Excision Repair by Controlling Steady-State Levels of DNA Polymerase β
DNA base excision repair (BER) is an essential cellular process required for genome stability, and misregulation of BER is linked to premature aging, increased rate of mutagenesis, and cancer. We have now identified the cytoplasmic ubiquitin-specific protease USP47 as the major enzyme involved in de...
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| Veröffentlicht in: | Molecular cell 2011-03, Vol.41 (5), p.609-615 |
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| creator | Parsons, Jason L. Dianova, Irina I. Khoronenkova, Svetlana V. Edelmann, Mariola J. Kessler, Benedikt M. Dianov, Grigory L. |
| description | DNA base excision repair (BER) is an essential cellular process required for genome stability, and misregulation of BER is linked to premature aging, increased rate of mutagenesis, and cancer. We have now identified the cytoplasmic ubiquitin-specific protease USP47 as the major enzyme involved in deubiquitylation of the key BER DNA polymerase (Pol β) and demonstrate that USP47 is required for stability of newly synthesized cytoplasmic Pol β that is used as a source for nuclear Pol β involved in DNA repair. We further show that knockdown of USP47 causes an increased level of ubiquitylated Pol β, decreased levels of Pol β, and a subsequent deficiency in BER, leading to accumulation of DNA strand breaks and decreased cell viability in response to DNA damage. Taken together, these data demonstrate an important role for USP47 in regulating DNA repair and maintaining genome integrity.
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► Cytoplasmic USP47 is the major human enzyme involved in Pol β deubiquitylation ► USP47 is required for stability of newly synthesized cytoplasmic Pol β ► USP47 knockdown decreases levels of Pol β and results in deficient DNA repair ► USP47 knockdown cells are sensitive to DNA-damaging agents |
| doi_str_mv | 10.1016/j.molcel.2011.02.016 |
| format | Article |
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► Cytoplasmic USP47 is the major human enzyme involved in Pol β deubiquitylation ► USP47 is required for stability of newly synthesized cytoplasmic Pol β ► USP47 knockdown decreases levels of Pol β and results in deficient DNA repair ► USP47 knockdown cells are sensitive to DNA-damaging agents</description><identifier>ISSN: 1097-2765</identifier><identifier>EISSN: 1097-4164</identifier><identifier>DOI: 10.1016/j.molcel.2011.02.016</identifier><identifier>PMID: 21362556</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Catalytic Domain ; Cytoplasm - metabolism ; DNA Damage ; DNA Polymerase beta - metabolism ; DNA Repair ; Gene Expression Regulation, Enzymologic ; Genome ; Glycosylation ; HeLa Cells ; Humans ; Lysine - chemistry ; Models, Biological ; Ubiquitin - chemistry ; Ubiquitin Thiolesterase - chemistry ; Ubiquitin Thiolesterase - physiology ; Ubiquitin-Specific Proteases</subject><ispartof>Molecular cell, 2011-03, Vol.41 (5), p.609-615</ispartof><rights>2011 Elsevier Inc.</rights><rights>Copyright © 2011 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c393t-7b2027db30cbd14fb0c268624355cdf255e384664cad8d028b4d4648246257d33</citedby><cites>FETCH-LOGICAL-c393t-7b2027db30cbd14fb0c268624355cdf255e384664cad8d028b4d4648246257d33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.molcel.2011.02.016$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21362556$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Parsons, Jason L.</creatorcontrib><creatorcontrib>Dianova, Irina I.</creatorcontrib><creatorcontrib>Khoronenkova, Svetlana V.</creatorcontrib><creatorcontrib>Edelmann, Mariola J.</creatorcontrib><creatorcontrib>Kessler, Benedikt M.</creatorcontrib><creatorcontrib>Dianov, Grigory L.</creatorcontrib><title>USP47 Is a Deubiquitylating Enzyme that Regulates Base Excision Repair by Controlling Steady-State Levels of DNA Polymerase β</title><title>Molecular cell</title><addtitle>Mol Cell</addtitle><description>DNA base excision repair (BER) is an essential cellular process required for genome stability, and misregulation of BER is linked to premature aging, increased rate of mutagenesis, and cancer. We have now identified the cytoplasmic ubiquitin-specific protease USP47 as the major enzyme involved in deubiquitylation of the key BER DNA polymerase (Pol β) and demonstrate that USP47 is required for stability of newly synthesized cytoplasmic Pol β that is used as a source for nuclear Pol β involved in DNA repair. We further show that knockdown of USP47 causes an increased level of ubiquitylated Pol β, decreased levels of Pol β, and a subsequent deficiency in BER, leading to accumulation of DNA strand breaks and decreased cell viability in response to DNA damage. Taken together, these data demonstrate an important role for USP47 in regulating DNA repair and maintaining genome integrity.
[Display omitted]
► Cytoplasmic USP47 is the major human enzyme involved in Pol β deubiquitylation ► USP47 is required for stability of newly synthesized cytoplasmic Pol β ► USP47 knockdown decreases levels of Pol β and results in deficient DNA repair ► USP47 knockdown cells are sensitive to DNA-damaging agents</description><subject>Catalytic Domain</subject><subject>Cytoplasm - metabolism</subject><subject>DNA Damage</subject><subject>DNA Polymerase beta - metabolism</subject><subject>DNA Repair</subject><subject>Gene Expression Regulation, Enzymologic</subject><subject>Genome</subject><subject>Glycosylation</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Lysine - chemistry</subject><subject>Models, Biological</subject><subject>Ubiquitin - chemistry</subject><subject>Ubiquitin Thiolesterase - chemistry</subject><subject>Ubiquitin Thiolesterase - physiology</subject><subject>Ubiquitin-Specific Proteases</subject><issn>1097-2765</issn><issn>1097-4164</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMFu1DAURS0EoqXwBwh5xyrBdhwn2SCV6QCVRlAxdG059kvxyImntlMRFnwUH8I34dEMLFm9p6t779M7CL2kpKSEije7cvROgysZobQkrMziI3ROSdcUnAr--LSzRtRn6FmMO0Ior9vuKTpjtBKsrsU5-nm7veENvo5Y4SuYe3s_27Q4lex0h9fTj2UEnL6phL_A3ZxliPidioDX37WN1k9Z3ysbcL_glZ9S8M4dktsEyizFNuUE3sADuIj9gK8-XeIb73JpOJT8_vUcPRmUi_DiNC_Q7fv119XHYvP5w_XqclPoqqtS0fSMsMb0FdG9oXzoiWaiFYxXda3NkF-BquVCcK1Mawhre2644C3j-c3GVNUFen3s3Qd_P0NMcrQxw3NqAj9H2RHOG067Jjv50amDjzHAIPfBjioskhJ5AC938gheHsBLwmQWc-zV6cDcj2D-hf6Szoa3R0NGAQ8WgozawqTB2AA6SePt_y_8ATzvlkY</recordid><startdate>20110304</startdate><enddate>20110304</enddate><creator>Parsons, Jason L.</creator><creator>Dianova, Irina I.</creator><creator>Khoronenkova, Svetlana V.</creator><creator>Edelmann, Mariola J.</creator><creator>Kessler, Benedikt M.</creator><creator>Dianov, Grigory L.</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>20110304</creationdate><title>USP47 Is a Deubiquitylating Enzyme that Regulates Base Excision Repair by Controlling Steady-State Levels of DNA Polymerase β</title><author>Parsons, Jason L. ; Dianova, Irina I. ; Khoronenkova, Svetlana V. ; Edelmann, Mariola J. ; Kessler, Benedikt M. ; Dianov, Grigory L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c393t-7b2027db30cbd14fb0c268624355cdf255e384664cad8d028b4d4648246257d33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Catalytic Domain</topic><topic>Cytoplasm - metabolism</topic><topic>DNA Damage</topic><topic>DNA Polymerase beta - metabolism</topic><topic>DNA Repair</topic><topic>Gene Expression Regulation, Enzymologic</topic><topic>Genome</topic><topic>Glycosylation</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>Lysine - chemistry</topic><topic>Models, Biological</topic><topic>Ubiquitin - chemistry</topic><topic>Ubiquitin Thiolesterase - chemistry</topic><topic>Ubiquitin Thiolesterase - physiology</topic><topic>Ubiquitin-Specific Proteases</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Parsons, Jason L.</creatorcontrib><creatorcontrib>Dianova, Irina I.</creatorcontrib><creatorcontrib>Khoronenkova, Svetlana V.</creatorcontrib><creatorcontrib>Edelmann, Mariola J.</creatorcontrib><creatorcontrib>Kessler, Benedikt M.</creatorcontrib><creatorcontrib>Dianov, Grigory L.</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>Molecular cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Parsons, Jason L.</au><au>Dianova, Irina I.</au><au>Khoronenkova, Svetlana V.</au><au>Edelmann, Mariola J.</au><au>Kessler, Benedikt M.</au><au>Dianov, Grigory L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>USP47 Is a Deubiquitylating Enzyme that Regulates Base Excision Repair by Controlling Steady-State Levels of DNA Polymerase β</atitle><jtitle>Molecular cell</jtitle><addtitle>Mol Cell</addtitle><date>2011-03-04</date><risdate>2011</risdate><volume>41</volume><issue>5</issue><spage>609</spage><epage>615</epage><pages>609-615</pages><issn>1097-2765</issn><eissn>1097-4164</eissn><abstract>DNA base excision repair (BER) is an essential cellular process required for genome stability, and misregulation of BER is linked to premature aging, increased rate of mutagenesis, and cancer. We have now identified the cytoplasmic ubiquitin-specific protease USP47 as the major enzyme involved in deubiquitylation of the key BER DNA polymerase (Pol β) and demonstrate that USP47 is required for stability of newly synthesized cytoplasmic Pol β that is used as a source for nuclear Pol β involved in DNA repair. We further show that knockdown of USP47 causes an increased level of ubiquitylated Pol β, decreased levels of Pol β, and a subsequent deficiency in BER, leading to accumulation of DNA strand breaks and decreased cell viability in response to DNA damage. Taken together, these data demonstrate an important role for USP47 in regulating DNA repair and maintaining genome integrity.
[Display omitted]
► Cytoplasmic USP47 is the major human enzyme involved in Pol β deubiquitylation ► USP47 is required for stability of newly synthesized cytoplasmic Pol β ► USP47 knockdown decreases levels of Pol β and results in deficient DNA repair ► USP47 knockdown cells are sensitive to DNA-damaging agents</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>21362556</pmid><doi>10.1016/j.molcel.2011.02.016</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Catalytic Domain Cytoplasm - metabolism DNA Damage DNA Polymerase beta - metabolism DNA Repair Gene Expression Regulation, Enzymologic Genome Glycosylation HeLa Cells Humans Lysine - chemistry Models, Biological Ubiquitin - chemistry Ubiquitin Thiolesterase - chemistry Ubiquitin Thiolesterase - physiology Ubiquitin-Specific Proteases |
| title | USP47 Is a Deubiquitylating Enzyme that Regulates Base Excision Repair by Controlling Steady-State Levels of DNA Polymerase β |
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