Benzo[a]pyrene represses DNA repair through altered E2F1/E2F4 function marking an early event in DNA damage-induced cellular senescence
Abstract Transcriptional regulation of DNA repair is of outmost importance for the restoration of DNA integrity upon genotoxic stress. Here we report that the potent environmental carcinogen benzo[a]pyrene (B[a]P) activates a cellular DNA damage response resulting in transcriptional repression of mi...
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| Veröffentlicht in: | Nucleic acids research 2020-12, Vol.48 (21), p.12085-12101 |
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| creator | Allmann, Sebastian Mayer, Laura Olma, Jessika Kaina, Bernd Hofmann, Thomas G Tomicic, Maja T Christmann, Markus |
| description | Abstract
Transcriptional regulation of DNA repair is of outmost importance for the restoration of DNA integrity upon genotoxic stress. Here we report that the potent environmental carcinogen benzo[a]pyrene (B[a]P) activates a cellular DNA damage response resulting in transcriptional repression of mismatch repair (MMR) genes (MSH2, MSH6, EXO1) and of RAD51, the central homologous recombination repair (HR) component, ultimately leading to downregulation of MMR and HR. B[a]P-induced gene repression is caused by abrogated E2F1 signalling. This occurs through proteasomal degradation of E2F1 in G2-arrested cells and downregulation of E2F1 mRNA expression in G1-arrested cells. Repression of E2F1-mediated transcription and silencing of repair genes is further mediated by the p21-dependent E2F4/DREAM complex. Notably, repression of DNA repair is also observed following exposure to the active B[a]P metabolite BPDE and upon ionizing radiation and occurs in response to a p53/p21-triggered, irreversible cell cycle arrest marking the onset of cellular senescence. Overall, our results suggest that repression of MMR and HR is an early event during genotoxic-stress induced senescence. We propose that persistent downregulation of DNA repair might play a role in the maintenance of the senescence phenotype, which is associated with an accumulation of unrepairable DNA lesions. |
| doi_str_mv | 10.1093/nar/gkaa965 |
| format | Article |
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Transcriptional regulation of DNA repair is of outmost importance for the restoration of DNA integrity upon genotoxic stress. Here we report that the potent environmental carcinogen benzo[a]pyrene (B[a]P) activates a cellular DNA damage response resulting in transcriptional repression of mismatch repair (MMR) genes (MSH2, MSH6, EXO1) and of RAD51, the central homologous recombination repair (HR) component, ultimately leading to downregulation of MMR and HR. B[a]P-induced gene repression is caused by abrogated E2F1 signalling. This occurs through proteasomal degradation of E2F1 in G2-arrested cells and downregulation of E2F1 mRNA expression in G1-arrested cells. Repression of E2F1-mediated transcription and silencing of repair genes is further mediated by the p21-dependent E2F4/DREAM complex. Notably, repression of DNA repair is also observed following exposure to the active B[a]P metabolite BPDE and upon ionizing radiation and occurs in response to a p53/p21-triggered, irreversible cell cycle arrest marking the onset of cellular senescence. Overall, our results suggest that repression of MMR and HR is an early event during genotoxic-stress induced senescence. We propose that persistent downregulation of DNA repair might play a role in the maintenance of the senescence phenotype, which is associated with an accumulation of unrepairable DNA lesions.</description><identifier>ISSN: 0305-1048</identifier><identifier>EISSN: 1362-4962</identifier><identifier>DOI: 10.1093/nar/gkaa965</identifier><identifier>PMID: 33166399</identifier><language>eng</language><publisher>OXFORD: Oxford University Press</publisher><subject>Benzo(a)pyrene - toxicity ; Biochemistry & Molecular Biology ; Carcinogens - toxicity ; Cell Cycle Checkpoints ; Cell Line, Transformed ; Cell Line, Tumor ; Cellular Senescence - genetics ; Cyclin-Dependent Kinase Inhibitor p21 - genetics ; Cyclin-Dependent Kinase Inhibitor p21 - metabolism ; DNA - genetics ; DNA - metabolism ; DNA Damage ; DNA Mismatch Repair - drug effects ; DNA Mismatch Repair - radiation effects ; DNA Repair Enzymes - genetics ; DNA Repair Enzymes - metabolism ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; E2F1 Transcription Factor - genetics ; E2F1 Transcription Factor - metabolism ; E2F4 Transcription Factor - genetics ; E2F4 Transcription Factor - metabolism ; Epithelial Cells - cytology ; Epithelial Cells - drug effects ; Epithelial Cells - metabolism ; Epithelial Cells - radiation effects ; Exodeoxyribonucleases - genetics ; Exodeoxyribonucleases - metabolism ; Fibroblasts - cytology ; Fibroblasts - drug effects ; Fibroblasts - metabolism ; Fibroblasts - radiation effects ; Gamma Rays ; Gene regulation, Chromatin and Epigenetics ; Humans ; Kv Channel-Interacting Proteins - genetics ; Kv Channel-Interacting Proteins - metabolism ; Life Sciences & Biomedicine ; MCF-7 Cells ; MutS Homolog 2 Protein - genetics ; MutS Homolog 2 Protein - metabolism ; Rad51 Recombinase - genetics ; Rad51 Recombinase - metabolism ; Recombinational DNA Repair - drug effects ; Recombinational DNA Repair - radiation effects ; Repressor Proteins - genetics ; Repressor Proteins - metabolism ; Science & Technology ; Signal Transduction</subject><ispartof>Nucleic acids research, 2020-12, Vol.48 (21), p.12085-12101</ispartof><rights>The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. 2020</rights><rights>The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>22</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000606018700026</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c342t-910cc0bfcd2b4d569ac4a023efd60469c1a1f654fde389d914ec79c2cb66a3c33</citedby><cites>FETCH-LOGICAL-c342t-910cc0bfcd2b4d569ac4a023efd60469c1a1f654fde389d914ec79c2cb66a3c33</cites><orcidid>0000-0001-9289-4168 ; 0000-0002-9672-231X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708059/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708059/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,1605,2115,27929,27930,28253,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33166399$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Allmann, Sebastian</creatorcontrib><creatorcontrib>Mayer, Laura</creatorcontrib><creatorcontrib>Olma, Jessika</creatorcontrib><creatorcontrib>Kaina, Bernd</creatorcontrib><creatorcontrib>Hofmann, Thomas G</creatorcontrib><creatorcontrib>Tomicic, Maja T</creatorcontrib><creatorcontrib>Christmann, Markus</creatorcontrib><title>Benzo[a]pyrene represses DNA repair through altered E2F1/E2F4 function marking an early event in DNA damage-induced cellular senescence</title><title>Nucleic acids research</title><addtitle>NUCLEIC ACIDS RES</addtitle><addtitle>Nucleic Acids Res</addtitle><description>Abstract
Transcriptional regulation of DNA repair is of outmost importance for the restoration of DNA integrity upon genotoxic stress. Here we report that the potent environmental carcinogen benzo[a]pyrene (B[a]P) activates a cellular DNA damage response resulting in transcriptional repression of mismatch repair (MMR) genes (MSH2, MSH6, EXO1) and of RAD51, the central homologous recombination repair (HR) component, ultimately leading to downregulation of MMR and HR. B[a]P-induced gene repression is caused by abrogated E2F1 signalling. This occurs through proteasomal degradation of E2F1 in G2-arrested cells and downregulation of E2F1 mRNA expression in G1-arrested cells. Repression of E2F1-mediated transcription and silencing of repair genes is further mediated by the p21-dependent E2F4/DREAM complex. Notably, repression of DNA repair is also observed following exposure to the active B[a]P metabolite BPDE and upon ionizing radiation and occurs in response to a p53/p21-triggered, irreversible cell cycle arrest marking the onset of cellular senescence. Overall, our results suggest that repression of MMR and HR is an early event during genotoxic-stress induced senescence. We propose that persistent downregulation of DNA repair might play a role in the maintenance of the senescence phenotype, which is associated with an accumulation of unrepairable DNA lesions.</description><subject>Benzo(a)pyrene - toxicity</subject><subject>Biochemistry & Molecular Biology</subject><subject>Carcinogens - toxicity</subject><subject>Cell Cycle Checkpoints</subject><subject>Cell Line, Transformed</subject><subject>Cell Line, Tumor</subject><subject>Cellular Senescence - genetics</subject><subject>Cyclin-Dependent Kinase Inhibitor p21 - genetics</subject><subject>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</subject><subject>DNA - genetics</subject><subject>DNA - metabolism</subject><subject>DNA Damage</subject><subject>DNA Mismatch Repair - drug effects</subject><subject>DNA Mismatch Repair - radiation effects</subject><subject>DNA Repair Enzymes - genetics</subject><subject>DNA Repair Enzymes - metabolism</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>E2F1 Transcription Factor - genetics</subject><subject>E2F1 Transcription Factor - metabolism</subject><subject>E2F4 Transcription Factor - genetics</subject><subject>E2F4 Transcription Factor - metabolism</subject><subject>Epithelial Cells - cytology</subject><subject>Epithelial Cells - drug effects</subject><subject>Epithelial Cells - metabolism</subject><subject>Epithelial Cells - radiation effects</subject><subject>Exodeoxyribonucleases - genetics</subject><subject>Exodeoxyribonucleases - metabolism</subject><subject>Fibroblasts - cytology</subject><subject>Fibroblasts - drug effects</subject><subject>Fibroblasts - metabolism</subject><subject>Fibroblasts - radiation effects</subject><subject>Gamma Rays</subject><subject>Gene regulation, Chromatin and Epigenetics</subject><subject>Humans</subject><subject>Kv Channel-Interacting Proteins - genetics</subject><subject>Kv Channel-Interacting Proteins - metabolism</subject><subject>Life Sciences & Biomedicine</subject><subject>MCF-7 Cells</subject><subject>MutS Homolog 2 Protein - genetics</subject><subject>MutS Homolog 2 Protein - metabolism</subject><subject>Rad51 Recombinase - genetics</subject><subject>Rad51 Recombinase - metabolism</subject><subject>Recombinational DNA Repair - drug effects</subject><subject>Recombinational DNA Repair - radiation effects</subject><subject>Repressor Proteins - genetics</subject><subject>Repressor Proteins - metabolism</subject><subject>Science & Technology</subject><subject>Signal Transduction</subject><issn>0305-1048</issn><issn>1362-4962</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>TOX</sourceid><sourceid>AOWDO</sourceid><sourceid>EIF</sourceid><recordid>eNqNUc-P1CAUJkbjzq6evBtOXkwdKJQpF5N13FWTjV70ZEzzCq8d3A400K6Z_Qf8t2WcddSLMSSPR_h-8PgIecLZC860WHqIy_4aQKvqHllwocpCalXeJwsmWFVwJusTcprSV8a45JV8SE6E4EoJrRfk-yv0t-EzfBl3ET3SiGPElDDR1-_P9ydwkU6bGOZ-Q2GYMKKlF-UlX-YiaTd7M7ng6RbitfM9BU8R4rCjeIN-os7_1LGwhR4L5-1sMt_gMMwDRJqyZTLoDT4iDzoYEj6-28_Ip8uLj-u3xdWHN-_W51eFEbKcCs2ZMaztjC1baSulwUhgpcDOKiaVNhx4pyrZWRS1tppLNCttStMqBcIIcUZeHnTHud2izd5ThKEZo8sT7JoArvn7xrtN04ebZrViNat0Fnh-EDAxpBSxO3I5a_Z5NDmP5i6PjH76p90R-yuA33LfsA1dMm7_GUcYY0zlxetV7kqV0fX_o9dugn026zD7KVOfHahhHv_55B8Ij7iP</recordid><startdate>20201202</startdate><enddate>20201202</enddate><creator>Allmann, Sebastian</creator><creator>Mayer, Laura</creator><creator>Olma, Jessika</creator><creator>Kaina, Bernd</creator><creator>Hofmann, Thomas G</creator><creator>Tomicic, Maja T</creator><creator>Christmann, Markus</creator><general>Oxford University Press</general><general>Oxford Univ Press</general><scope>TOX</scope><scope>AOWDO</scope><scope>BLEPL</scope><scope>DTL</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>5PM</scope><orcidid>https://orcid.org/0000-0001-9289-4168</orcidid><orcidid>https://orcid.org/0000-0002-9672-231X</orcidid></search><sort><creationdate>20201202</creationdate><title>Benzo[a]pyrene represses DNA repair through altered E2F1/E2F4 function marking an early event in DNA damage-induced cellular senescence</title><author>Allmann, Sebastian ; Mayer, Laura ; Olma, Jessika ; Kaina, Bernd ; Hofmann, Thomas G ; Tomicic, Maja T ; Christmann, Markus</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c342t-910cc0bfcd2b4d569ac4a023efd60469c1a1f654fde389d914ec79c2cb66a3c33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Benzo(a)pyrene - toxicity</topic><topic>Biochemistry & Molecular Biology</topic><topic>Carcinogens - toxicity</topic><topic>Cell Cycle Checkpoints</topic><topic>Cell Line, Transformed</topic><topic>Cell Line, Tumor</topic><topic>Cellular Senescence - genetics</topic><topic>Cyclin-Dependent Kinase Inhibitor p21 - genetics</topic><topic>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</topic><topic>DNA - genetics</topic><topic>DNA - metabolism</topic><topic>DNA Damage</topic><topic>DNA Mismatch Repair - drug effects</topic><topic>DNA Mismatch Repair - radiation effects</topic><topic>DNA Repair Enzymes - genetics</topic><topic>DNA Repair Enzymes - metabolism</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>E2F1 Transcription Factor - genetics</topic><topic>E2F1 Transcription Factor - metabolism</topic><topic>E2F4 Transcription Factor - genetics</topic><topic>E2F4 Transcription Factor - metabolism</topic><topic>Epithelial Cells - cytology</topic><topic>Epithelial Cells - drug effects</topic><topic>Epithelial Cells - metabolism</topic><topic>Epithelial Cells - radiation effects</topic><topic>Exodeoxyribonucleases - genetics</topic><topic>Exodeoxyribonucleases - metabolism</topic><topic>Fibroblasts - cytology</topic><topic>Fibroblasts - drug effects</topic><topic>Fibroblasts - metabolism</topic><topic>Fibroblasts - radiation effects</topic><topic>Gamma Rays</topic><topic>Gene regulation, Chromatin and Epigenetics</topic><topic>Humans</topic><topic>Kv Channel-Interacting Proteins - genetics</topic><topic>Kv Channel-Interacting Proteins - metabolism</topic><topic>Life Sciences & Biomedicine</topic><topic>MCF-7 Cells</topic><topic>MutS Homolog 2 Protein - genetics</topic><topic>MutS Homolog 2 Protein - metabolism</topic><topic>Rad51 Recombinase - genetics</topic><topic>Rad51 Recombinase - metabolism</topic><topic>Recombinational DNA Repair - drug effects</topic><topic>Recombinational DNA Repair - radiation effects</topic><topic>Repressor Proteins - genetics</topic><topic>Repressor Proteins - metabolism</topic><topic>Science & Technology</topic><topic>Signal Transduction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Allmann, Sebastian</creatorcontrib><creatorcontrib>Mayer, Laura</creatorcontrib><creatorcontrib>Olma, Jessika</creatorcontrib><creatorcontrib>Kaina, Bernd</creatorcontrib><creatorcontrib>Hofmann, Thomas G</creatorcontrib><creatorcontrib>Tomicic, Maja T</creatorcontrib><creatorcontrib>Christmann, Markus</creatorcontrib><collection>Access via Oxford University Press (Open Access Collection)</collection><collection>Web of Science - Science Citation Index Expanded - 2020</collection><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nucleic acids research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Allmann, Sebastian</au><au>Mayer, Laura</au><au>Olma, Jessika</au><au>Kaina, Bernd</au><au>Hofmann, Thomas G</au><au>Tomicic, Maja T</au><au>Christmann, Markus</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Benzo[a]pyrene represses DNA repair through altered E2F1/E2F4 function marking an early event in DNA damage-induced cellular senescence</atitle><jtitle>Nucleic acids research</jtitle><stitle>NUCLEIC ACIDS RES</stitle><addtitle>Nucleic Acids Res</addtitle><date>2020-12-02</date><risdate>2020</risdate><volume>48</volume><issue>21</issue><spage>12085</spage><epage>12101</epage><pages>12085-12101</pages><issn>0305-1048</issn><eissn>1362-4962</eissn><abstract>Abstract
Transcriptional regulation of DNA repair is of outmost importance for the restoration of DNA integrity upon genotoxic stress. Here we report that the potent environmental carcinogen benzo[a]pyrene (B[a]P) activates a cellular DNA damage response resulting in transcriptional repression of mismatch repair (MMR) genes (MSH2, MSH6, EXO1) and of RAD51, the central homologous recombination repair (HR) component, ultimately leading to downregulation of MMR and HR. B[a]P-induced gene repression is caused by abrogated E2F1 signalling. This occurs through proteasomal degradation of E2F1 in G2-arrested cells and downregulation of E2F1 mRNA expression in G1-arrested cells. Repression of E2F1-mediated transcription and silencing of repair genes is further mediated by the p21-dependent E2F4/DREAM complex. Notably, repression of DNA repair is also observed following exposure to the active B[a]P metabolite BPDE and upon ionizing radiation and occurs in response to a p53/p21-triggered, irreversible cell cycle arrest marking the onset of cellular senescence. Overall, our results suggest that repression of MMR and HR is an early event during genotoxic-stress induced senescence. We propose that persistent downregulation of DNA repair might play a role in the maintenance of the senescence phenotype, which is associated with an accumulation of unrepairable DNA lesions.</abstract><cop>OXFORD</cop><pub>Oxford University Press</pub><pmid>33166399</pmid><doi>10.1093/nar/gkaa965</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0001-9289-4168</orcidid><orcidid>https://orcid.org/0000-0002-9672-231X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Benzo(a)pyrene - toxicity Biochemistry & Molecular Biology Carcinogens - toxicity Cell Cycle Checkpoints Cell Line, Transformed Cell Line, Tumor Cellular Senescence - genetics Cyclin-Dependent Kinase Inhibitor p21 - genetics Cyclin-Dependent Kinase Inhibitor p21 - metabolism DNA - genetics DNA - metabolism DNA Damage DNA Mismatch Repair - drug effects DNA Mismatch Repair - radiation effects DNA Repair Enzymes - genetics DNA Repair Enzymes - metabolism DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism E2F1 Transcription Factor - genetics E2F1 Transcription Factor - metabolism E2F4 Transcription Factor - genetics E2F4 Transcription Factor - metabolism Epithelial Cells - cytology Epithelial Cells - drug effects Epithelial Cells - metabolism Epithelial Cells - radiation effects Exodeoxyribonucleases - genetics Exodeoxyribonucleases - metabolism Fibroblasts - cytology Fibroblasts - drug effects Fibroblasts - metabolism Fibroblasts - radiation effects Gamma Rays Gene regulation, Chromatin and Epigenetics Humans Kv Channel-Interacting Proteins - genetics Kv Channel-Interacting Proteins - metabolism Life Sciences & Biomedicine MCF-7 Cells MutS Homolog 2 Protein - genetics MutS Homolog 2 Protein - metabolism Rad51 Recombinase - genetics Rad51 Recombinase - metabolism Recombinational DNA Repair - drug effects Recombinational DNA Repair - radiation effects Repressor Proteins - genetics Repressor Proteins - metabolism Science & Technology Signal Transduction |
| title | Benzo[a]pyrene represses DNA repair through altered E2F1/E2F4 function marking an early event in DNA damage-induced cellular senescence |
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