Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites
Imbalance in the level of the pyrimidine degradation products dihydrouracil and dihydrothymine is associated with cellular transformation and cancer progression. Dihydropyrimidines are degraded by dihydropyrimidinase (DHP), a zinc metalloenzyme that is upregulated in solid tumors but not in the corr...
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| Veröffentlicht in: | Nucleic acids research 2020-02, Vol.48 (4), p.1886-1904 |
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| creator | Basbous, Jihane Aze, Antoine Chaloin, Laurent Lebdy, Rana Hodroj, Dana Ribeyre, Cyril Larroque, Marion Shepard, Caitlin Kim, Baek Pruvost, Alain Moreaux, Jérôme Maiorano, Domenico Mechali, Marcel Constantinou, Angelos |
| description | Imbalance in the level of the pyrimidine degradation products dihydrouracil and dihydrothymine is associated with cellular transformation and cancer progression. Dihydropyrimidines are degraded by dihydropyrimidinase (DHP), a zinc metalloenzyme that is upregulated in solid tumors but not in the corresponding normal tissues. How dihydropyrimidine metabolites affect cellular phenotypes remains elusive. Here we show that the accumulation of dihydropyrimidines induces the formation of DNA-protein crosslinks (DPCs) and causes DNA replication and transcriptional stress. We used Xenopus egg extracts to recapitulate DNA replication invitro. We found that dihydropyrimidines interfere directly with the replication of both plasmid and chromosomal DNA. Furthermore, we show that the plant flavonoid dihydromyricetin inhibits human DHP activity. Cellular exposure to dihydromyricetin triggered DPCs-dependent DNA replication stress in cancer cells. This study defines dihydropyrimidines as potentially cytotoxic metabolites that may offer an opportunity for therapeutic-targeting of DHP activity in solid tumors. |
| doi_str_mv | 10.1093/nar/gkz1162 |
| format | Article |
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Dihydropyrimidines are degraded by dihydropyrimidinase (DHP), a zinc metalloenzyme that is upregulated in solid tumors but not in the corresponding normal tissues. How dihydropyrimidine metabolites affect cellular phenotypes remains elusive. Here we show that the accumulation of dihydropyrimidines induces the formation of DNA-protein crosslinks (DPCs) and causes DNA replication and transcriptional stress. We used Xenopus egg extracts to recapitulate DNA replication invitro. We found that dihydropyrimidines interfere directly with the replication of both plasmid and chromosomal DNA. Furthermore, we show that the plant flavonoid dihydromyricetin inhibits human DHP activity. Cellular exposure to dihydromyricetin triggered DPCs-dependent DNA replication stress in cancer cells. This study defines dihydropyrimidines as potentially cytotoxic metabolites that may offer an opportunity for therapeutic-targeting of DHP activity in solid tumors.</description><identifier>ISSN: 0305-1048</identifier><identifier>EISSN: 1362-4962</identifier><identifier>DOI: 10.1093/nar/gkz1162</identifier><identifier>PMID: 31853544</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Amidohydrolases - genetics ; Animals ; Antineoplastic Agents - therapeutic use ; Biochemistry, Molecular Biology ; Cell Transformation, Neoplastic - genetics ; DNA Replication - genetics ; Genome Integrity, Repair and ; Humans ; Life Sciences ; Neoplasms - drug therapy ; Neoplasms - genetics ; Transcription, Genetic ; Uracil - analogs & derivatives ; Uracil - metabolism ; Xenopus laevis - genetics ; Xenopus laevis - growth & development</subject><ispartof>Nucleic acids research, 2020-02, Vol.48 (4), p.1886-1904</ispartof><rights>The Author(s) 2019. 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Published by Oxford University Press on behalf of Nucleic Acids Research. 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c481t-f089afaa2ffec2dc9aa13e7fea4e46e2e3bbd44565cc83323ef4177ebd8c87213</citedby><cites>FETCH-LOGICAL-c481t-f089afaa2ffec2dc9aa13e7fea4e46e2e3bbd44565cc83323ef4177ebd8c87213</cites><orcidid>0000-0002-5717-3207 ; 0000-0002-2994-8140 ; 0000-0002-5146-0977 ; 0000-0002-7781-7735 ; 0000-0002-3943-627X ; 0000-0002-5757-5804 ; 0000-0001-7986-4335</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/PMC7038975/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038975/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27923,27924,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31853544$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-02556387$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Basbous, Jihane</creatorcontrib><creatorcontrib>Aze, Antoine</creatorcontrib><creatorcontrib>Chaloin, Laurent</creatorcontrib><creatorcontrib>Lebdy, Rana</creatorcontrib><creatorcontrib>Hodroj, Dana</creatorcontrib><creatorcontrib>Ribeyre, Cyril</creatorcontrib><creatorcontrib>Larroque, Marion</creatorcontrib><creatorcontrib>Shepard, Caitlin</creatorcontrib><creatorcontrib>Kim, Baek</creatorcontrib><creatorcontrib>Pruvost, Alain</creatorcontrib><creatorcontrib>Moreaux, Jérôme</creatorcontrib><creatorcontrib>Maiorano, Domenico</creatorcontrib><creatorcontrib>Mechali, Marcel</creatorcontrib><creatorcontrib>Constantinou, Angelos</creatorcontrib><title>Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites</title><title>Nucleic acids research</title><addtitle>Nucleic Acids Res</addtitle><description>Imbalance in the level of the pyrimidine degradation products dihydrouracil and dihydrothymine is associated with cellular transformation and cancer progression. Dihydropyrimidines are degraded by dihydropyrimidinase (DHP), a zinc metalloenzyme that is upregulated in solid tumors but not in the corresponding normal tissues. How dihydropyrimidine metabolites affect cellular phenotypes remains elusive. Here we show that the accumulation of dihydropyrimidines induces the formation of DNA-protein crosslinks (DPCs) and causes DNA replication and transcriptional stress. We used Xenopus egg extracts to recapitulate DNA replication invitro. We found that dihydropyrimidines interfere directly with the replication of both plasmid and chromosomal DNA. Furthermore, we show that the plant flavonoid dihydromyricetin inhibits human DHP activity. Cellular exposure to dihydromyricetin triggered DPCs-dependent DNA replication stress in cancer cells. This study defines dihydropyrimidines as potentially cytotoxic metabolites that may offer an opportunity for therapeutic-targeting of DHP activity in solid tumors.</description><subject>Amidohydrolases - genetics</subject><subject>Animals</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Biochemistry, Molecular Biology</subject><subject>Cell Transformation, Neoplastic - genetics</subject><subject>DNA Replication - genetics</subject><subject>Genome Integrity, Repair and</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - genetics</subject><subject>Transcription, Genetic</subject><subject>Uracil - analogs & derivatives</subject><subject>Uracil - metabolism</subject><subject>Xenopus laevis - genetics</subject><subject>Xenopus laevis - growth & development</subject><issn>0305-1048</issn><issn>1362-4962</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc1v1DAQxS0EokvhxB35SIVC_Rk7F6RVCxRp1V5A4mY5zrhrSOJgeyvCX9-sdqmgp5FmfvOenh5Cryl5T0nDz0ebzm9__qG0Zk_QivKaVaKp2VO0IpzIihKhT9CLnH8QQgWV4jk64VRLLoVYoe-XYTt3KU5zCkPowmgz4CnFAq5k7FMc8OX1GieY-uBsCXHEuSTIGTu7y9DhdsZuLrHE38HhAYptYx8K5Jfombd9hlfHeYq-ffr49eKq2tx8_nKx3lROaFoqT3RjvbXMe3Csc421lIPyYAWIGhjwtu2EkLV0TnPOOHhBlYK2004rRvkp-nDQnXbtAJ2DsSTbm2mJY9Nsog3m_8sYtuY23hlFuG6UXATODgLbR29X643Z7wiTsuZa3e3N3h7NUvy1g1zMELKDvrcjxF02jDOtpFRKLOi7A-pSzDmBf9CmxOx7M0tv5tjbQr_5N8UD-7cofg84iZgF</recordid><startdate>20200228</startdate><enddate>20200228</enddate><creator>Basbous, Jihane</creator><creator>Aze, Antoine</creator><creator>Chaloin, Laurent</creator><creator>Lebdy, Rana</creator><creator>Hodroj, Dana</creator><creator>Ribeyre, Cyril</creator><creator>Larroque, Marion</creator><creator>Shepard, Caitlin</creator><creator>Kim, Baek</creator><creator>Pruvost, Alain</creator><creator>Moreaux, Jérôme</creator><creator>Maiorano, Domenico</creator><creator>Mechali, Marcel</creator><creator>Constantinou, Angelos</creator><general>Oxford University Press</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>1XC</scope><scope>VOOES</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-5717-3207</orcidid><orcidid>https://orcid.org/0000-0002-2994-8140</orcidid><orcidid>https://orcid.org/0000-0002-5146-0977</orcidid><orcidid>https://orcid.org/0000-0002-7781-7735</orcidid><orcidid>https://orcid.org/0000-0002-3943-627X</orcidid><orcidid>https://orcid.org/0000-0002-5757-5804</orcidid><orcidid>https://orcid.org/0000-0001-7986-4335</orcidid></search><sort><creationdate>20200228</creationdate><title>Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites</title><author>Basbous, Jihane ; Aze, Antoine ; Chaloin, Laurent ; Lebdy, Rana ; Hodroj, Dana ; Ribeyre, Cyril ; Larroque, Marion ; Shepard, Caitlin ; Kim, Baek ; Pruvost, Alain ; Moreaux, Jérôme ; Maiorano, Domenico ; Mechali, Marcel ; Constantinou, Angelos</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c481t-f089afaa2ffec2dc9aa13e7fea4e46e2e3bbd44565cc83323ef4177ebd8c87213</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Amidohydrolases - genetics</topic><topic>Animals</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Biochemistry, Molecular Biology</topic><topic>Cell Transformation, Neoplastic - genetics</topic><topic>DNA Replication - genetics</topic><topic>Genome Integrity, Repair and</topic><topic>Humans</topic><topic>Life Sciences</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - genetics</topic><topic>Transcription, Genetic</topic><topic>Uracil - analogs & derivatives</topic><topic>Uracil - metabolism</topic><topic>Xenopus laevis - genetics</topic><topic>Xenopus laevis - growth & development</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Basbous, Jihane</creatorcontrib><creatorcontrib>Aze, Antoine</creatorcontrib><creatorcontrib>Chaloin, Laurent</creatorcontrib><creatorcontrib>Lebdy, Rana</creatorcontrib><creatorcontrib>Hodroj, Dana</creatorcontrib><creatorcontrib>Ribeyre, Cyril</creatorcontrib><creatorcontrib>Larroque, Marion</creatorcontrib><creatorcontrib>Shepard, Caitlin</creatorcontrib><creatorcontrib>Kim, Baek</creatorcontrib><creatorcontrib>Pruvost, Alain</creatorcontrib><creatorcontrib>Moreaux, Jérôme</creatorcontrib><creatorcontrib>Maiorano, Domenico</creatorcontrib><creatorcontrib>Mechali, Marcel</creatorcontrib><creatorcontrib>Constantinou, Angelos</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>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</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>Basbous, Jihane</au><au>Aze, Antoine</au><au>Chaloin, Laurent</au><au>Lebdy, Rana</au><au>Hodroj, Dana</au><au>Ribeyre, Cyril</au><au>Larroque, Marion</au><au>Shepard, Caitlin</au><au>Kim, Baek</au><au>Pruvost, Alain</au><au>Moreaux, Jérôme</au><au>Maiorano, Domenico</au><au>Mechali, Marcel</au><au>Constantinou, Angelos</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites</atitle><jtitle>Nucleic acids research</jtitle><addtitle>Nucleic Acids Res</addtitle><date>2020-02-28</date><risdate>2020</risdate><volume>48</volume><issue>4</issue><spage>1886</spage><epage>1904</epage><pages>1886-1904</pages><issn>0305-1048</issn><eissn>1362-4962</eissn><abstract>Imbalance in the level of the pyrimidine degradation products dihydrouracil and dihydrothymine is associated with cellular transformation and cancer progression. Dihydropyrimidines are degraded by dihydropyrimidinase (DHP), a zinc metalloenzyme that is upregulated in solid tumors but not in the corresponding normal tissues. How dihydropyrimidine metabolites affect cellular phenotypes remains elusive. Here we show that the accumulation of dihydropyrimidines induces the formation of DNA-protein crosslinks (DPCs) and causes DNA replication and transcriptional stress. We used Xenopus egg extracts to recapitulate DNA replication invitro. We found that dihydropyrimidines interfere directly with the replication of both plasmid and chromosomal DNA. Furthermore, we show that the plant flavonoid dihydromyricetin inhibits human DHP activity. Cellular exposure to dihydromyricetin triggered DPCs-dependent DNA replication stress in cancer cells. This study defines dihydropyrimidines as potentially cytotoxic metabolites that may offer an opportunity for therapeutic-targeting of DHP activity in solid tumors.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>31853544</pmid><doi>10.1093/nar/gkz1162</doi><tpages>19</tpages><orcidid>https://orcid.org/0000-0002-5717-3207</orcidid><orcidid>https://orcid.org/0000-0002-2994-8140</orcidid><orcidid>https://orcid.org/0000-0002-5146-0977</orcidid><orcidid>https://orcid.org/0000-0002-7781-7735</orcidid><orcidid>https://orcid.org/0000-0002-3943-627X</orcidid><orcidid>https://orcid.org/0000-0002-5757-5804</orcidid><orcidid>https://orcid.org/0000-0001-7986-4335</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Amidohydrolases - genetics Animals Antineoplastic Agents - therapeutic use Biochemistry, Molecular Biology Cell Transformation, Neoplastic - genetics DNA Replication - genetics Genome Integrity, Repair and Humans Life Sciences Neoplasms - drug therapy Neoplasms - genetics Transcription, Genetic Uracil - analogs & derivatives Uracil - metabolism Xenopus laevis - genetics Xenopus laevis - growth & development |
| title | Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites |
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