ELOF1 is a transcription-coupled DNA repair factor that directs RNA polymerase II ubiquitylation
Cells employ transcription-coupled repair (TCR) to eliminate transcription-blocking DNA lesions. DNA damage-induced binding of the TCR-specific repair factor CSB to RNA polymerase II (RNAPII) triggers RNAPII ubiquitylation of a single lysine (K1268) by the CRL4 CSA ubiquitin ligase. How CRL4 CSA is...
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| Veröffentlicht in: | Nature cell biology 2021-06, Vol.23 (6), p.595-607 |
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| creator | van der Weegen, Yana de Lint, Klaas van den Heuvel, Diana Nakazawa, Yuka Mevissen, Tycho E. T. van Schie, Janne J. M. San Martin Alonso, Marta Boer, Daphne E. C. González-Prieto, Román Narayanan, Ishwarya V. Klaassen, Noud H. M. Wondergem, Annelotte P. Roohollahi, Khashayar Dorsman, Josephine C. Hara, Yuichiro Vertegaal, Alfred C. O. de Lange, Job Walter, Johannes C. Noordermeer, Sylvie M. Ljungman, Mats Ogi, Tomoo Wolthuis, Rob M. F. Luijsterburg, Martijn S. |
| description | Cells employ transcription-coupled repair (TCR) to eliminate transcription-blocking DNA lesions. DNA damage-induced binding of the TCR-specific repair factor CSB to RNA polymerase II (RNAPII) triggers RNAPII ubiquitylation of a single lysine (K1268) by the CRL4
CSA
ubiquitin ligase. How CRL4
CSA
is specifically directed towards K1268 is unknown. Here, we identify ELOF1 as the missing link that facilitates RNAPII ubiquitylation, a key signal for the assembly of downstream repair factors. This function requires its constitutive interaction with RNAPII close to K1268, revealing ELOF1 as a specificity factor that binds and positions CRL4
CSA
for optimal RNAPII ubiquitylation. Drug–genetic interaction screening also revealed a CSB-independent pathway in which ELOF1 prevents R-loops in active genes and protects cells against DNA replication stress. Our study offers key insights into the molecular mechanisms of TCR and provides a genetic framework of the interplay between transcriptional stress responses and DNA replication.
Two side-by-side papers report that the transcription elongation factor ELOF1 drives transcription-coupled repair and prevents replication stress. |
| doi_str_mv | 10.1038/s41556-021-00688-9 |
| format | Article |
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CSA
ubiquitin ligase. How CRL4
CSA
is specifically directed towards K1268 is unknown. Here, we identify ELOF1 as the missing link that facilitates RNAPII ubiquitylation, a key signal for the assembly of downstream repair factors. This function requires its constitutive interaction with RNAPII close to K1268, revealing ELOF1 as a specificity factor that binds and positions CRL4
CSA
for optimal RNAPII ubiquitylation. Drug–genetic interaction screening also revealed a CSB-independent pathway in which ELOF1 prevents R-loops in active genes and protects cells against DNA replication stress. Our study offers key insights into the molecular mechanisms of TCR and provides a genetic framework of the interplay between transcriptional stress responses and DNA replication.
Two side-by-side papers report that the transcription elongation factor ELOF1 drives transcription-coupled repair and prevents replication stress.</description><identifier>ISSN: 1465-7392</identifier><identifier>EISSN: 1476-4679</identifier><identifier>DOI: 10.1038/s41556-021-00688-9</identifier><identifier>PMID: 34108663</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 14 ; 38 ; 45 ; 631/337/1427 ; 631/337/151 ; 631/337/572 ; 631/80/458/582 ; 82 ; Biomedical and Life Sciences ; Cancer Research ; Cell Biology ; Cell Line, Tumor ; Cellular stress response ; CRISPR-Cas Systems ; Deoxyribonucleic acid ; Developmental Biology ; DNA ; DNA biosynthesis ; DNA Damage ; DNA Helicases - genetics ; DNA Helicases - metabolism ; DNA Repair ; DNA Repair Enzymes - genetics ; DNA Repair Enzymes - metabolism ; DNA-directed RNA polymerase ; Elongation ; Genetic screening ; Humans ; Life Sciences ; Lysine ; Molecular modelling ; Peptide Elongation Factor 1 - genetics ; Peptide Elongation Factor 1 - metabolism ; Poly-ADP-Ribose Binding Proteins - genetics ; Poly-ADP-Ribose Binding Proteins - metabolism ; Protein Binding ; Protein Interaction Domains and Motifs ; R-loops ; Repair ; Replication ; Ribonucleic acid ; RNA ; RNA polymerase ; RNA polymerase II ; RNA Polymerase II - genetics ; RNA Polymerase II - metabolism ; Stem Cells ; Transcription Elongation, Genetic ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Transcription-coupled repair ; Ubiquitin ; Ubiquitin-protein ligase ; Ubiquitin-Protein Ligases - genetics ; Ubiquitin-Protein Ligases - metabolism ; Ubiquitination</subject><ispartof>Nature cell biology, 2021-06, Vol.23 (6), p.595-607</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021</rights><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-70314ceb9e33847abf08af3de5f7352939a78f8bf9d3e1d2c12aaed85b57f70d3</citedby><cites>FETCH-LOGICAL-c474t-70314ceb9e33847abf08af3de5f7352939a78f8bf9d3e1d2c12aaed85b57f70d3</cites><orcidid>0000-0002-2324-5292 ; 0000-0002-9002-8829 ; 0000-0002-3109-1588 ; 0000-0003-2737-9690 ; 0000-0003-1553-6695 ; 0000-0002-5492-9072 ; 0000-0001-5796-6541 ; 0000-0002-4186-7570 ; 0000-0001-8997-2321</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41556-021-00688-9$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41556-021-00688-9$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,777,781,882,27905,27906,41469,42538,51300</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34108663$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>van der Weegen, Yana</creatorcontrib><creatorcontrib>de Lint, Klaas</creatorcontrib><creatorcontrib>van den Heuvel, Diana</creatorcontrib><creatorcontrib>Nakazawa, Yuka</creatorcontrib><creatorcontrib>Mevissen, Tycho E. T.</creatorcontrib><creatorcontrib>van Schie, Janne J. M.</creatorcontrib><creatorcontrib>San Martin Alonso, Marta</creatorcontrib><creatorcontrib>Boer, Daphne E. C.</creatorcontrib><creatorcontrib>González-Prieto, Román</creatorcontrib><creatorcontrib>Narayanan, Ishwarya V.</creatorcontrib><creatorcontrib>Klaassen, Noud H. M.</creatorcontrib><creatorcontrib>Wondergem, Annelotte P.</creatorcontrib><creatorcontrib>Roohollahi, Khashayar</creatorcontrib><creatorcontrib>Dorsman, Josephine C.</creatorcontrib><creatorcontrib>Hara, Yuichiro</creatorcontrib><creatorcontrib>Vertegaal, Alfred C. O.</creatorcontrib><creatorcontrib>de Lange, Job</creatorcontrib><creatorcontrib>Walter, Johannes C.</creatorcontrib><creatorcontrib>Noordermeer, Sylvie M.</creatorcontrib><creatorcontrib>Ljungman, Mats</creatorcontrib><creatorcontrib>Ogi, Tomoo</creatorcontrib><creatorcontrib>Wolthuis, Rob M. F.</creatorcontrib><creatorcontrib>Luijsterburg, Martijn S.</creatorcontrib><title>ELOF1 is a transcription-coupled DNA repair factor that directs RNA polymerase II ubiquitylation</title><title>Nature cell biology</title><addtitle>Nat Cell Biol</addtitle><addtitle>Nat Cell Biol</addtitle><description>Cells employ transcription-coupled repair (TCR) to eliminate transcription-blocking DNA lesions. DNA damage-induced binding of the TCR-specific repair factor CSB to RNA polymerase II (RNAPII) triggers RNAPII ubiquitylation of a single lysine (K1268) by the CRL4
CSA
ubiquitin ligase. How CRL4
CSA
is specifically directed towards K1268 is unknown. Here, we identify ELOF1 as the missing link that facilitates RNAPII ubiquitylation, a key signal for the assembly of downstream repair factors. This function requires its constitutive interaction with RNAPII close to K1268, revealing ELOF1 as a specificity factor that binds and positions CRL4
CSA
for optimal RNAPII ubiquitylation. Drug–genetic interaction screening also revealed a CSB-independent pathway in which ELOF1 prevents R-loops in active genes and protects cells against DNA replication stress. Our study offers key insights into the molecular mechanisms of TCR and provides a genetic framework of the interplay between transcriptional stress responses and DNA replication.
Two side-by-side papers report that the transcription elongation factor ELOF1 drives transcription-coupled repair and prevents replication stress.</description><subject>13</subject><subject>14</subject><subject>38</subject><subject>45</subject><subject>631/337/1427</subject><subject>631/337/151</subject><subject>631/337/572</subject><subject>631/80/458/582</subject><subject>82</subject><subject>Biomedical and Life Sciences</subject><subject>Cancer Research</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Cellular stress response</subject><subject>CRISPR-Cas Systems</subject><subject>Deoxyribonucleic acid</subject><subject>Developmental Biology</subject><subject>DNA</subject><subject>DNA biosynthesis</subject><subject>DNA Damage</subject><subject>DNA Helicases - genetics</subject><subject>DNA Helicases - metabolism</subject><subject>DNA Repair</subject><subject>DNA Repair Enzymes - genetics</subject><subject>DNA Repair Enzymes - metabolism</subject><subject>DNA-directed RNA polymerase</subject><subject>Elongation</subject><subject>Genetic screening</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Lysine</subject><subject>Molecular modelling</subject><subject>Peptide Elongation Factor 1 - genetics</subject><subject>Peptide Elongation Factor 1 - metabolism</subject><subject>Poly-ADP-Ribose Binding Proteins - genetics</subject><subject>Poly-ADP-Ribose Binding Proteins - metabolism</subject><subject>Protein Binding</subject><subject>Protein Interaction Domains and Motifs</subject><subject>R-loops</subject><subject>Repair</subject><subject>Replication</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA polymerase</subject><subject>RNA polymerase II</subject><subject>RNA Polymerase II - genetics</subject><subject>RNA Polymerase II - metabolism</subject><subject>Stem Cells</subject><subject>Transcription Elongation, Genetic</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Transcription-coupled repair</subject><subject>Ubiquitin</subject><subject>Ubiquitin-protein ligase</subject><subject>Ubiquitin-Protein Ligases - genetics</subject><subject>Ubiquitin-Protein Ligases - metabolism</subject><subject>Ubiquitination</subject><issn>1465-7392</issn><issn>1476-4679</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kUtPJCEUhYnR-Jr5Ay4MiWsUCqqAjYnRVjvpaDKZWTMUBYqpLkqgTPrfS9s-Zjau7k3O4buHHACOCD4lmIqzxEhdNwhXBGHcCIHkFtgnjDeINVxur_emRpzKag8cpPSEMWEM812wRxnBomnoPvg7W9xfE-gT1DBHPSQT_Zh9GJAJ09jbDl7dXcBoR-0jdNrkEGF-1Bl2PlqTE_xV5DH0q6WNOlk4n8Op9c-Tz6terzk_wI7TfbI_3-ch-HM9-315ixb3N_PLiwUyjLOMOKaEGdtKS6lgXLcOC-1oZ2vHaV1JKjUXTrROdtSSrjKk0tp2om5r7jju6CE433DHqV3aztihfKdXY_RLHVcqaK_-Vwb_qB7CixJCYt7IAjh5B8TwPNmU1VOY4lAyq6qmJYCQlBRXtXGZGFKK1n1eIFitW1GbVlRpRb21otbo43-zfT75qKEY6MaQijQ82Ph1-xvsK-LDmao</recordid><startdate>20210601</startdate><enddate>20210601</enddate><creator>van der Weegen, Yana</creator><creator>de Lint, Klaas</creator><creator>van den Heuvel, Diana</creator><creator>Nakazawa, Yuka</creator><creator>Mevissen, Tycho E. 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T. ; van Schie, Janne J. M. ; San Martin Alonso, Marta ; Boer, Daphne E. C. ; González-Prieto, Román ; Narayanan, Ishwarya V. ; Klaassen, Noud H. M. ; Wondergem, Annelotte P. ; Roohollahi, Khashayar ; Dorsman, Josephine C. ; Hara, Yuichiro ; Vertegaal, Alfred C. O. ; de Lange, Job ; Walter, Johannes C. ; Noordermeer, Sylvie M. ; Ljungman, Mats ; Ogi, Tomoo ; Wolthuis, Rob M. 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F.</creatorcontrib><creatorcontrib>Luijsterburg, Martijn S.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature cell biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>van der Weegen, Yana</au><au>de Lint, Klaas</au><au>van den Heuvel, Diana</au><au>Nakazawa, Yuka</au><au>Mevissen, Tycho E. T.</au><au>van Schie, Janne J. M.</au><au>San Martin Alonso, Marta</au><au>Boer, Daphne E. C.</au><au>González-Prieto, Román</au><au>Narayanan, Ishwarya V.</au><au>Klaassen, Noud H. M.</au><au>Wondergem, Annelotte P.</au><au>Roohollahi, Khashayar</au><au>Dorsman, Josephine C.</au><au>Hara, Yuichiro</au><au>Vertegaal, Alfred C. O.</au><au>de Lange, Job</au><au>Walter, Johannes C.</au><au>Noordermeer, Sylvie M.</au><au>Ljungman, Mats</au><au>Ogi, Tomoo</au><au>Wolthuis, Rob M. F.</au><au>Luijsterburg, Martijn S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>ELOF1 is a transcription-coupled DNA repair factor that directs RNA polymerase II ubiquitylation</atitle><jtitle>Nature cell biology</jtitle><stitle>Nat Cell Biol</stitle><addtitle>Nat Cell Biol</addtitle><date>2021-06-01</date><risdate>2021</risdate><volume>23</volume><issue>6</issue><spage>595</spage><epage>607</epage><pages>595-607</pages><issn>1465-7392</issn><eissn>1476-4679</eissn><abstract>Cells employ transcription-coupled repair (TCR) to eliminate transcription-blocking DNA lesions. DNA damage-induced binding of the TCR-specific repair factor CSB to RNA polymerase II (RNAPII) triggers RNAPII ubiquitylation of a single lysine (K1268) by the CRL4
CSA
ubiquitin ligase. How CRL4
CSA
is specifically directed towards K1268 is unknown. Here, we identify ELOF1 as the missing link that facilitates RNAPII ubiquitylation, a key signal for the assembly of downstream repair factors. This function requires its constitutive interaction with RNAPII close to K1268, revealing ELOF1 as a specificity factor that binds and positions CRL4
CSA
for optimal RNAPII ubiquitylation. Drug–genetic interaction screening also revealed a CSB-independent pathway in which ELOF1 prevents R-loops in active genes and protects cells against DNA replication stress. Our study offers key insights into the molecular mechanisms of TCR and provides a genetic framework of the interplay between transcriptional stress responses and DNA replication.
Two side-by-side papers report that the transcription elongation factor ELOF1 drives transcription-coupled repair and prevents replication stress.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>34108663</pmid><doi>10.1038/s41556-021-00688-9</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-2324-5292</orcidid><orcidid>https://orcid.org/0000-0002-9002-8829</orcidid><orcidid>https://orcid.org/0000-0002-3109-1588</orcidid><orcidid>https://orcid.org/0000-0003-2737-9690</orcidid><orcidid>https://orcid.org/0000-0003-1553-6695</orcidid><orcidid>https://orcid.org/0000-0002-5492-9072</orcidid><orcidid>https://orcid.org/0000-0001-5796-6541</orcidid><orcidid>https://orcid.org/0000-0002-4186-7570</orcidid><orcidid>https://orcid.org/0000-0001-8997-2321</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1465-7392 |
| ispartof | Nature cell biology, 2021-06, Vol.23 (6), p.595-607 |
| issn | 1465-7392 1476-4679 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8890769 |
| source | MEDLINE; SpringerLink Journals; Nature Journals Online |
| subjects | 13 14 38 45 631/337/1427 631/337/151 631/337/572 631/80/458/582 82 Biomedical and Life Sciences Cancer Research Cell Biology Cell Line, Tumor Cellular stress response CRISPR-Cas Systems Deoxyribonucleic acid Developmental Biology DNA DNA biosynthesis DNA Damage DNA Helicases - genetics DNA Helicases - metabolism DNA Repair DNA Repair Enzymes - genetics DNA Repair Enzymes - metabolism DNA-directed RNA polymerase Elongation Genetic screening Humans Life Sciences Lysine Molecular modelling Peptide Elongation Factor 1 - genetics Peptide Elongation Factor 1 - metabolism Poly-ADP-Ribose Binding Proteins - genetics Poly-ADP-Ribose Binding Proteins - metabolism Protein Binding Protein Interaction Domains and Motifs R-loops Repair Replication Ribonucleic acid RNA RNA polymerase RNA polymerase II RNA Polymerase II - genetics RNA Polymerase II - metabolism Stem Cells Transcription Elongation, Genetic Transcription Factors - genetics Transcription Factors - metabolism Transcription-coupled repair Ubiquitin Ubiquitin-protein ligase Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism Ubiquitination |
| title | ELOF1 is a transcription-coupled DNA repair factor that directs RNA polymerase II ubiquitylation |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-19T05%3A15%3A01IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=ELOF1%20is%20a%20transcription-coupled%20DNA%20repair%20factor%20that%20directs%20RNA%20polymerase%20II%20ubiquitylation&rft.jtitle=Nature%20cell%20biology&rft.au=van%20der%20Weegen,%20Yana&rft.date=2021-06-01&rft.volume=23&rft.issue=6&rft.spage=595&rft.epage=607&rft.pages=595-607&rft.issn=1465-7392&rft.eissn=1476-4679&rft_id=info:doi/10.1038/s41556-021-00688-9&rft_dat=%3Cproquest_pubme%3E2539398931%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2539398931&rft_id=info:pmid/34108663&rfr_iscdi=true |