TREX1 degrades the 3′ end of the small DNA oligonucleotide products of nucleotide excision repair in human cells
Abstract The nucleotide excision repair (NER) machinery removes UV photoproducts from DNA in the form of small, excised damage-containing DNA oligonucleotides (sedDNAs) ∼30 nt in length. How cells process and degrade these byproducts of DNA repair is not known. Using a small scale RNA interference s...
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Veröffentlicht in: | Nucleic acids research 2022-04, Vol.50 (7), p.3974-3984 |
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creator | Kim, Seon Hee Kim, Geun Hoe Kemp, Michael G Choi, Jun-Hyuk |
description | Abstract
The nucleotide excision repair (NER) machinery removes UV photoproducts from DNA in the form of small, excised damage-containing DNA oligonucleotides (sedDNAs) ∼30 nt in length. How cells process and degrade these byproducts of DNA repair is not known. Using a small scale RNA interference screen in UV-irradiated human cells, we identified TREX1 as a major regulator of sedDNA abundance. Knockdown of TREX1 increased the level of sedDNAs containing the two major UV photoproducts and their association with the NER proteins TFIIH and RPA. Overexpression of wild-type but not nuclease-inactive TREX1 significantly diminished sedDNA levels, and studies with purified recombinant TREX1 showed that the enzyme efficiently degrades DNA located 3′ of the UV photoproduct in the sedDNA. Knockdown or overexpression of TREX1 did not impact the overall rate of UV photoproduct removal from genomic DNA or cell survival, which indicates that TREX1 function in sedDNA degradation does not impact NER efficiency. Taken together, these results indicate a previously unknown role for TREX1 in promoting the degradation of the sedDNA products of the repair reaction. Because TREX1 mutations and inefficient DNA degradation impact inflammatory and immune signaling pathways, the regulation of sedDNA degradation by TREX1 may contribute to photosensitive skin disorders. |
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The nucleotide excision repair (NER) machinery removes UV photoproducts from DNA in the form of small, excised damage-containing DNA oligonucleotides (sedDNAs) ∼30 nt in length. How cells process and degrade these byproducts of DNA repair is not known. Using a small scale RNA interference screen in UV-irradiated human cells, we identified TREX1 as a major regulator of sedDNA abundance. Knockdown of TREX1 increased the level of sedDNAs containing the two major UV photoproducts and their association with the NER proteins TFIIH and RPA. Overexpression of wild-type but not nuclease-inactive TREX1 significantly diminished sedDNA levels, and studies with purified recombinant TREX1 showed that the enzyme efficiently degrades DNA located 3′ of the UV photoproduct in the sedDNA. Knockdown or overexpression of TREX1 did not impact the overall rate of UV photoproduct removal from genomic DNA or cell survival, which indicates that TREX1 function in sedDNA degradation does not impact NER efficiency. Taken together, these results indicate a previously unknown role for TREX1 in promoting the degradation of the sedDNA products of the repair reaction. Because TREX1 mutations and inefficient DNA degradation impact inflammatory and immune signaling pathways, the regulation of sedDNA degradation by TREX1 may contribute to photosensitive skin disorders.</description><identifier>ISSN: 0305-1048</identifier><identifier>EISSN: 1362-4962</identifier><identifier>DOI: 10.1093/nar/gkac214</identifier><identifier>PMID: 35357486</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>DNA Damage ; DNA Repair ; Exodeoxyribonucleases - metabolism ; Genome Integrity, Repair and ; Humans ; Oligonucleotides - metabolism ; Phosphoproteins - metabolism ; Ultraviolet Rays</subject><ispartof>Nucleic acids research, 2022-04, Vol.50 (7), p.3974-3984</ispartof><rights>The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. 2022</rights><rights>The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c412t-dbdf645792f4c64321961cf0443bac9739736bfc3584743c1251054125af26ef3</citedby><cites>FETCH-LOGICAL-c412t-dbdf645792f4c64321961cf0443bac9739736bfc3584743c1251054125af26ef3</cites><orcidid>0000-0001-8203-0745</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/PMC9023299/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9023299/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,1598,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35357486$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Seon Hee</creatorcontrib><creatorcontrib>Kim, Geun Hoe</creatorcontrib><creatorcontrib>Kemp, Michael G</creatorcontrib><creatorcontrib>Choi, Jun-Hyuk</creatorcontrib><title>TREX1 degrades the 3′ end of the small DNA oligonucleotide products of nucleotide excision repair in human cells</title><title>Nucleic acids research</title><addtitle>Nucleic Acids Res</addtitle><description>Abstract
The nucleotide excision repair (NER) machinery removes UV photoproducts from DNA in the form of small, excised damage-containing DNA oligonucleotides (sedDNAs) ∼30 nt in length. How cells process and degrade these byproducts of DNA repair is not known. Using a small scale RNA interference screen in UV-irradiated human cells, we identified TREX1 as a major regulator of sedDNA abundance. Knockdown of TREX1 increased the level of sedDNAs containing the two major UV photoproducts and their association with the NER proteins TFIIH and RPA. Overexpression of wild-type but not nuclease-inactive TREX1 significantly diminished sedDNA levels, and studies with purified recombinant TREX1 showed that the enzyme efficiently degrades DNA located 3′ of the UV photoproduct in the sedDNA. Knockdown or overexpression of TREX1 did not impact the overall rate of UV photoproduct removal from genomic DNA or cell survival, which indicates that TREX1 function in sedDNA degradation does not impact NER efficiency. Taken together, these results indicate a previously unknown role for TREX1 in promoting the degradation of the sedDNA products of the repair reaction. Because TREX1 mutations and inefficient DNA degradation impact inflammatory and immune signaling pathways, the regulation of sedDNA degradation by TREX1 may contribute to photosensitive skin disorders.</description><subject>DNA Damage</subject><subject>DNA Repair</subject><subject>Exodeoxyribonucleases - metabolism</subject><subject>Genome Integrity, Repair and</subject><subject>Humans</subject><subject>Oligonucleotides - metabolism</subject><subject>Phosphoproteins - metabolism</subject><subject>Ultraviolet Rays</subject><issn>0305-1048</issn><issn>1362-4962</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>TOX</sourceid><sourceid>EIF</sourceid><recordid>eNp9kM1Kw0AUhQdRbK2u3Mus3Ejs_CbNRii1_kBRkAruwmQyk44mmTCTiO58Jh_JJzG1tdSNcOFy7_3OuXAAOMboHKOYDivhhvmLkASzHdDHNCQBi0OyC_qIIh5gxEY9cOD9M0KYYc72QY9yyiM2CvvAzR-mTxhmKnciUx42CwXp18cnVFUGrf6ZfSmKAl7ejaEtTG6rVhbKNiZTsHY2a2Xjl-TWWr1J442toFO1MA6aCi7aUlRQqqLwh2BPi8Kro3UfgMer6XxyE8zur28n41kgGSZNkKWZDhmPYqKZDBklOA6x1IgxmgoZR7SrMNWS8hGLGJWYcIx4J-VCk1BpOgAXK9-6TUuVSVU1ThRJ7Uwp3HtihUn-XiqzSHL7msSIUBLHncHZykA6671TeqPFKFlGn3TRJ-voO_pk-92G_c26A05XgG3rf52-AXoDj6c</recordid><startdate>20220422</startdate><enddate>20220422</enddate><creator>Kim, Seon Hee</creator><creator>Kim, Geun Hoe</creator><creator>Kemp, Michael G</creator><creator>Choi, Jun-Hyuk</creator><general>Oxford University Press</general><scope>TOX</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/0000-0001-8203-0745</orcidid></search><sort><creationdate>20220422</creationdate><title>TREX1 degrades the 3′ end of the small DNA oligonucleotide products of nucleotide excision repair in human cells</title><author>Kim, Seon Hee ; Kim, Geun Hoe ; Kemp, Michael G ; Choi, Jun-Hyuk</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c412t-dbdf645792f4c64321961cf0443bac9739736bfc3584743c1251054125af26ef3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>DNA Damage</topic><topic>DNA Repair</topic><topic>Exodeoxyribonucleases - metabolism</topic><topic>Genome Integrity, Repair and</topic><topic>Humans</topic><topic>Oligonucleotides - metabolism</topic><topic>Phosphoproteins - metabolism</topic><topic>Ultraviolet Rays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, Seon Hee</creatorcontrib><creatorcontrib>Kim, Geun Hoe</creatorcontrib><creatorcontrib>Kemp, Michael G</creatorcontrib><creatorcontrib>Choi, Jun-Hyuk</creatorcontrib><collection>Oxford Journals Open Access Collection</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>Kim, Seon Hee</au><au>Kim, Geun Hoe</au><au>Kemp, Michael G</au><au>Choi, Jun-Hyuk</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TREX1 degrades the 3′ end of the small DNA oligonucleotide products of nucleotide excision repair in human cells</atitle><jtitle>Nucleic acids research</jtitle><addtitle>Nucleic Acids Res</addtitle><date>2022-04-22</date><risdate>2022</risdate><volume>50</volume><issue>7</issue><spage>3974</spage><epage>3984</epage><pages>3974-3984</pages><issn>0305-1048</issn><eissn>1362-4962</eissn><abstract>Abstract
The nucleotide excision repair (NER) machinery removes UV photoproducts from DNA in the form of small, excised damage-containing DNA oligonucleotides (sedDNAs) ∼30 nt in length. How cells process and degrade these byproducts of DNA repair is not known. Using a small scale RNA interference screen in UV-irradiated human cells, we identified TREX1 as a major regulator of sedDNA abundance. Knockdown of TREX1 increased the level of sedDNAs containing the two major UV photoproducts and their association with the NER proteins TFIIH and RPA. Overexpression of wild-type but not nuclease-inactive TREX1 significantly diminished sedDNA levels, and studies with purified recombinant TREX1 showed that the enzyme efficiently degrades DNA located 3′ of the UV photoproduct in the sedDNA. Knockdown or overexpression of TREX1 did not impact the overall rate of UV photoproduct removal from genomic DNA or cell survival, which indicates that TREX1 function in sedDNA degradation does not impact NER efficiency. Taken together, these results indicate a previously unknown role for TREX1 in promoting the degradation of the sedDNA products of the repair reaction. Because TREX1 mutations and inefficient DNA degradation impact inflammatory and immune signaling pathways, the regulation of sedDNA degradation by TREX1 may contribute to photosensitive skin disorders.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>35357486</pmid><doi>10.1093/nar/gkac214</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-8203-0745</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | DNA Damage DNA Repair Exodeoxyribonucleases - metabolism Genome Integrity, Repair and Humans Oligonucleotides - metabolism Phosphoproteins - metabolism Ultraviolet Rays |
title | TREX1 degrades the 3′ end of the small DNA oligonucleotide products of nucleotide excision repair in human cells |
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