ERK3 regulates TDP2-mediated DNA damage response and chemoresistance in lung cancer cells
Posttranslational modifications (PTMs), such as phosphorylation and ubiquitination, play critical regulatory roles in the assembly of DNA damage response proteins on the DNA damage site and their activities in DNA damage repair. Tyrosyl DNA phosphodiesterase 2 (TDP2) repairs Topoisomerase 2 (Top2)-l...
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| Veröffentlicht in: | Oncotarget 2016-02, Vol.7 (6), p.6665-6675 |
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| creator | Bian, Ka Muppani, Naveen Reddy Elkhadragy, Lobna Wang, Wei Zhang, Cheng Chen, Tenghui Jung, Sungyun Seternes, Ole Morten Long, Weiwen |
| description | Posttranslational modifications (PTMs), such as phosphorylation and ubiquitination, play critical regulatory roles in the assembly of DNA damage response proteins on the DNA damage site and their activities in DNA damage repair. Tyrosyl DNA phosphodiesterase 2 (TDP2) repairs Topoisomerase 2 (Top2)-linked DNA damage, thereby protecting cancer cells against Top2 inhibitors-induced growth inhibition and cell death. The regulation of TDP2 activity by post-translational modifications in DNA repair, however, remains unclear. In the current study, we have found that ERK3, an atypical MAPK, phosphorylates TDP2 at S60 and regulates TDP2's phosphodiesterase activity, thereby cooperatively protecting lung cancer cells against Top2 inhibitors-induced DNA damage and growth inhibition. As such, our study revealed a post-translational regulation of TDP2 activity and discovered a new role of ERK3 in increasing cancer cells' DNA damage response and chemoresistance to Top2 inhibitors. |
| doi_str_mv | 10.18632/oncotarget.6682 |
| format | Article |
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Tyrosyl DNA phosphodiesterase 2 (TDP2) repairs Topoisomerase 2 (Top2)-linked DNA damage, thereby protecting cancer cells against Top2 inhibitors-induced growth inhibition and cell death. The regulation of TDP2 activity by post-translational modifications in DNA repair, however, remains unclear. In the current study, we have found that ERK3, an atypical MAPK, phosphorylates TDP2 at S60 and regulates TDP2's phosphodiesterase activity, thereby cooperatively protecting lung cancer cells against Top2 inhibitors-induced DNA damage and growth inhibition. As such, our study revealed a post-translational regulation of TDP2 activity and discovered a new role of ERK3 in increasing cancer cells' DNA damage response and chemoresistance to Top2 inhibitors.</description><identifier>ISSN: 1949-2553</identifier><identifier>EISSN: 1949-2553</identifier><identifier>DOI: 10.18632/oncotarget.6682</identifier><identifier>PMID: 26701725</identifier><language>eng</language><publisher>United States: Impact journals</publisher><subject>Animals ; Antigens, Neoplasm - genetics ; Antigens, Neoplasm - metabolism ; Cell Line, Tumor ; DNA Damage ; DNA Topoisomerases, Type II - genetics ; DNA Topoisomerases, Type II - metabolism ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Drug Resistance, Neoplasm ; Etoposide - pharmacology ; HEK293 Cells ; Humans ; Lung Neoplasms - drug therapy ; Lung Neoplasms - genetics ; Lung Neoplasms - metabolism ; Mitogen-Activated Protein Kinase 6 - genetics ; Mitogen-Activated Protein Kinase 6 - metabolism ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; Phosphorylation ; Poly-ADP-Ribose Binding Proteins ; Protein Processing, Post-Translational ; Research Paper ; Sf9 Cells ; Topoisomerase II Inhibitors - pharmacology ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Transfection</subject><ispartof>Oncotarget, 2016-02, Vol.7 (6), p.6665-6675</ispartof><rights>info:eu-repo/semantics/openAccess</rights><rights>Copyright: © 2016 Bian et al. 2016</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c490t-346095eab490afb846c13e302b6420a376db317c83daed6329ad5b05692dbc973</citedby><cites>FETCH-LOGICAL-c490t-346095eab490afb846c13e302b6420a376db317c83daed6329ad5b05692dbc973</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872741/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872741/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,26544,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26701725$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bian, Ka</creatorcontrib><creatorcontrib>Muppani, Naveen Reddy</creatorcontrib><creatorcontrib>Elkhadragy, Lobna</creatorcontrib><creatorcontrib>Wang, Wei</creatorcontrib><creatorcontrib>Zhang, Cheng</creatorcontrib><creatorcontrib>Chen, Tenghui</creatorcontrib><creatorcontrib>Jung, Sungyun</creatorcontrib><creatorcontrib>Seternes, Ole Morten</creatorcontrib><creatorcontrib>Long, Weiwen</creatorcontrib><title>ERK3 regulates TDP2-mediated DNA damage response and chemoresistance in lung cancer cells</title><title>Oncotarget</title><addtitle>Oncotarget</addtitle><description>Posttranslational modifications (PTMs), such as phosphorylation and ubiquitination, play critical regulatory roles in the assembly of DNA damage response proteins on the DNA damage site and their activities in DNA damage repair. Tyrosyl DNA phosphodiesterase 2 (TDP2) repairs Topoisomerase 2 (Top2)-linked DNA damage, thereby protecting cancer cells against Top2 inhibitors-induced growth inhibition and cell death. The regulation of TDP2 activity by post-translational modifications in DNA repair, however, remains unclear. In the current study, we have found that ERK3, an atypical MAPK, phosphorylates TDP2 at S60 and regulates TDP2's phosphodiesterase activity, thereby cooperatively protecting lung cancer cells against Top2 inhibitors-induced DNA damage and growth inhibition. As such, our study revealed a post-translational regulation of TDP2 activity and discovered a new role of ERK3 in increasing cancer cells' DNA damage response and chemoresistance to Top2 inhibitors.</description><subject>Animals</subject><subject>Antigens, Neoplasm - genetics</subject><subject>Antigens, Neoplasm - metabolism</subject><subject>Cell Line, Tumor</subject><subject>DNA Damage</subject><subject>DNA Topoisomerases, Type II - genetics</subject><subject>DNA Topoisomerases, Type II - metabolism</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Drug Resistance, Neoplasm</subject><subject>Etoposide - pharmacology</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Lung Neoplasms - genetics</subject><subject>Lung Neoplasms - metabolism</subject><subject>Mitogen-Activated Protein Kinase 6 - genetics</subject><subject>Mitogen-Activated Protein Kinase 6 - metabolism</subject><subject>Nuclear Proteins - genetics</subject><subject>Nuclear Proteins - metabolism</subject><subject>Phosphorylation</subject><subject>Poly-ADP-Ribose Binding Proteins</subject><subject>Protein Processing, Post-Translational</subject><subject>Research Paper</subject><subject>Sf9 Cells</subject><subject>Topoisomerase II Inhibitors - pharmacology</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Transfection</subject><issn>1949-2553</issn><issn>1949-2553</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>3HK</sourceid><recordid>eNpVUUtP3jAQtFArQJR7T-BjL6F-xU4uSAjoQyBAFT30ZG3s_UJQYn-1k0r99_XHu77YY-_OzngI-cjZEW-0FJ9jcHGG1ON8pHUjtsgub1VbibqW796cd8h-zvesrFqZRrTbZEdow7gR9S75df7jQtKE_TLCjJnent2IakI_FOTp2dUJ9TBBj6Ukr2PISCF46u5wiuVmyDMEh3QIdFxCT90GJepwHPMH8n4FY8b9p32P_Pxyfnv6rbq8_vr99OSycqplcyWVZm2N0BUEq65R2nGJkolOK8FAGu07yY1rpAf0xXYLvu5YrVvhO9cauUeOH3nXS1eEOwxzgtGu0zBB-msjDPb_lzDc2T7-saoxwiheCA4fCVwqfoZgQ0xgOWPSWCHLz5aKT08jUvy9YJ7tNOSNSQgYl2y5MboIZWpTyp7JYs4JVy9COLMPsdnX2OwmttJy8NbAS8NzSPIfFMGVAQ</recordid><startdate>20160209</startdate><enddate>20160209</enddate><creator>Bian, Ka</creator><creator>Muppani, Naveen Reddy</creator><creator>Elkhadragy, Lobna</creator><creator>Wang, Wei</creator><creator>Zhang, Cheng</creator><creator>Chen, Tenghui</creator><creator>Jung, Sungyun</creator><creator>Seternes, Ole Morten</creator><creator>Long, Weiwen</creator><general>Impact journals</general><general>Impact Journals LLC</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>7X8</scope><scope>3HK</scope><scope>5PM</scope></search><sort><creationdate>20160209</creationdate><title>ERK3 regulates TDP2-mediated DNA damage response and chemoresistance in lung cancer cells</title><author>Bian, Ka ; Muppani, Naveen Reddy ; Elkhadragy, Lobna ; Wang, Wei ; Zhang, Cheng ; Chen, Tenghui ; Jung, Sungyun ; Seternes, Ole Morten ; Long, Weiwen</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c490t-346095eab490afb846c13e302b6420a376db317c83daed6329ad5b05692dbc973</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Antigens, Neoplasm - genetics</topic><topic>Antigens, Neoplasm - metabolism</topic><topic>Cell Line, Tumor</topic><topic>DNA Damage</topic><topic>DNA Topoisomerases, Type II - genetics</topic><topic>DNA Topoisomerases, Type II - metabolism</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Drug Resistance, Neoplasm</topic><topic>Etoposide - pharmacology</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Lung Neoplasms - genetics</topic><topic>Lung Neoplasms - metabolism</topic><topic>Mitogen-Activated Protein Kinase 6 - genetics</topic><topic>Mitogen-Activated Protein Kinase 6 - metabolism</topic><topic>Nuclear Proteins - genetics</topic><topic>Nuclear Proteins - metabolism</topic><topic>Phosphorylation</topic><topic>Poly-ADP-Ribose Binding Proteins</topic><topic>Protein Processing, Post-Translational</topic><topic>Research Paper</topic><topic>Sf9 Cells</topic><topic>Topoisomerase II Inhibitors - pharmacology</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><topic>Transfection</topic><toplevel>online_resources</toplevel><creatorcontrib>Bian, Ka</creatorcontrib><creatorcontrib>Muppani, Naveen Reddy</creatorcontrib><creatorcontrib>Elkhadragy, Lobna</creatorcontrib><creatorcontrib>Wang, Wei</creatorcontrib><creatorcontrib>Zhang, Cheng</creatorcontrib><creatorcontrib>Chen, Tenghui</creatorcontrib><creatorcontrib>Jung, Sungyun</creatorcontrib><creatorcontrib>Seternes, Ole Morten</creatorcontrib><creatorcontrib>Long, Weiwen</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>NORA - Norwegian Open Research Archives</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncotarget</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bian, Ka</au><au>Muppani, Naveen Reddy</au><au>Elkhadragy, Lobna</au><au>Wang, Wei</au><au>Zhang, Cheng</au><au>Chen, Tenghui</au><au>Jung, Sungyun</au><au>Seternes, Ole Morten</au><au>Long, Weiwen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>ERK3 regulates TDP2-mediated DNA damage response and chemoresistance in lung cancer cells</atitle><jtitle>Oncotarget</jtitle><addtitle>Oncotarget</addtitle><date>2016-02-09</date><risdate>2016</risdate><volume>7</volume><issue>6</issue><spage>6665</spage><epage>6675</epage><pages>6665-6675</pages><issn>1949-2553</issn><eissn>1949-2553</eissn><abstract>Posttranslational modifications (PTMs), such as phosphorylation and ubiquitination, play critical regulatory roles in the assembly of DNA damage response proteins on the DNA damage site and their activities in DNA damage repair. Tyrosyl DNA phosphodiesterase 2 (TDP2) repairs Topoisomerase 2 (Top2)-linked DNA damage, thereby protecting cancer cells against Top2 inhibitors-induced growth inhibition and cell death. The regulation of TDP2 activity by post-translational modifications in DNA repair, however, remains unclear. In the current study, we have found that ERK3, an atypical MAPK, phosphorylates TDP2 at S60 and regulates TDP2's phosphodiesterase activity, thereby cooperatively protecting lung cancer cells against Top2 inhibitors-induced DNA damage and growth inhibition. As such, our study revealed a post-translational regulation of TDP2 activity and discovered a new role of ERK3 in increasing cancer cells' DNA damage response and chemoresistance to Top2 inhibitors.</abstract><cop>United States</cop><pub>Impact journals</pub><pmid>26701725</pmid><doi>10.18632/oncotarget.6682</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antigens, Neoplasm - genetics Antigens, Neoplasm - metabolism Cell Line, Tumor DNA Damage DNA Topoisomerases, Type II - genetics DNA Topoisomerases, Type II - metabolism DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Drug Resistance, Neoplasm Etoposide - pharmacology HEK293 Cells Humans Lung Neoplasms - drug therapy Lung Neoplasms - genetics Lung Neoplasms - metabolism Mitogen-Activated Protein Kinase 6 - genetics Mitogen-Activated Protein Kinase 6 - metabolism Nuclear Proteins - genetics Nuclear Proteins - metabolism Phosphorylation Poly-ADP-Ribose Binding Proteins Protein Processing, Post-Translational Research Paper Sf9 Cells Topoisomerase II Inhibitors - pharmacology Transcription Factors - genetics Transcription Factors - metabolism Transfection |
| title | ERK3 regulates TDP2-mediated DNA damage response and chemoresistance in lung cancer cells |
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