Oocytes can efficiently repair DNA double-strand breaks to restore genetic integrity and protect offspring health
Female fertility and offspring health are critically dependent on an adequate supply of high-quality oocytes, the majority of which are maintained in the ovaries in a unique state of meiotic prophase arrest. While mechanisms of DNA repair during meiotic recombination are well characterized, the same...
Gespeichert in:
| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2020-05, Vol.117 (21), p.11513-11522 |
|---|---|
| Hauptverfasser: | , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 11522 |
|---|---|
| container_issue | 21 |
| container_start_page | 11513 |
| container_title | Proceedings of the National Academy of Sciences - PNAS |
| container_volume | 117 |
| creator | Stringer, Jessica M. Winship, Amy Zerafa, Nadeen Wakefield, Matthew Hutt, Karla |
| description | Female fertility and offspring health are critically dependent on an adequate supply of high-quality oocytes, the majority of which are maintained in the ovaries in a unique state of meiotic prophase arrest. While mechanisms of DNA repair during meiotic recombination are well characterized, the same is not true for prophase-arrested oocytes. Here we show that prophase-arrested oocytes rapidly respond to γ-irradiation–induced DNA double-strand breaks by activating Ataxia Telangiectasia Mutated, phosphorylating histone H2AX, and localizing RAD51 to the sites of DNA damage. Despite mobilizing the DNA repair response, even very low levels of DNA damage result in the apoptosis of prophase-arrested oocytes. However, we show that, when apoptosis is inhibited, severe DNA damage is corrected via homologous recombination repair. The repair is sufficient to support fertility and maintain health and genetic fidelity in offspring. Thus, despite the preferential induction of apoptosis following exogenously induced genotoxic stress, prophase-arrested oocytes are highly capable of functionally efficient DNA repair. These data implicate DNA repair as a key quality control mechanism in the female germ line and a critical determinant of fertility and genetic integrity. |
| doi_str_mv | 10.1073/pnas.2001124117 |
| format | Article |
| fullrecord | <record><control><sourceid>jstor_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7260990</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><jstor_id>26930975</jstor_id><sourcerecordid>26930975</sourcerecordid><originalsourceid>FETCH-LOGICAL-c509t-c6b0911af912db287dce36a87b143406c4d130e8415a9a9409ad7a48106e6bc13</originalsourceid><addsrcrecordid>eNpdkUtv1DAUhSMEotPCmhXIEptu0l4_EscbpKo8pYpuYG05zs2Mh4w9tR2k-fc4mjI8Vndxv3N0jk5VvaJwRUHy67036YoBUMoEpfJJtaKgaN0KBU-rFQCTdSeYOKvOU9oCgGo6eF6dccY7KgVdVQ_3wR4yJmKNJziOzjr0eTqQiHvjInn_9YYMYe4nrFOOxg-kj2h-JJJDQVIOEckaPWZnifMZ19HlA1m4fQwZbSZhHNM-Or8mGzRT3ryono1mSvjy8V5U3z9--Hb7ub67__Tl9uautg2oXNu2L02oGRVlQ886OVjkrelkTwUX0FoxUA7YCdoYZZQAZQZpREehxba3lF9U746--7nfYVH7kn_SJcrOxIMOxul_P95t9Dr81JK1oBQUg8tHgxge5tJV71yyOE3GY5iTZgKg4Z3s2oK-_Q_dhjn6Um-hJBesaWShro-UjSGliOMpDAW9zKmXOfWfOYvizd8dTvzv_Qrw-ghslylOf9YqDko2_BcKcKcK</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2407342557</pqid></control><display><type>article</type><title>Oocytes can efficiently repair DNA double-strand breaks to restore genetic integrity and protect offspring health</title><source>PubMed Central (Open Access)</source><source>Alma/SFX Local Collection</source><source>Free Full-Text Journals in Chemistry</source><source>JSTOR</source><creator>Stringer, Jessica M. ; Winship, Amy ; Zerafa, Nadeen ; Wakefield, Matthew ; Hutt, Karla</creator><creatorcontrib>Stringer, Jessica M. ; Winship, Amy ; Zerafa, Nadeen ; Wakefield, Matthew ; Hutt, Karla</creatorcontrib><description>Female fertility and offspring health are critically dependent on an adequate supply of high-quality oocytes, the majority of which are maintained in the ovaries in a unique state of meiotic prophase arrest. While mechanisms of DNA repair during meiotic recombination are well characterized, the same is not true for prophase-arrested oocytes. Here we show that prophase-arrested oocytes rapidly respond to γ-irradiation–induced DNA double-strand breaks by activating Ataxia Telangiectasia Mutated, phosphorylating histone H2AX, and localizing RAD51 to the sites of DNA damage. Despite mobilizing the DNA repair response, even very low levels of DNA damage result in the apoptosis of prophase-arrested oocytes. However, we show that, when apoptosis is inhibited, severe DNA damage is corrected via homologous recombination repair. The repair is sufficient to support fertility and maintain health and genetic fidelity in offspring. Thus, despite the preferential induction of apoptosis following exogenously induced genotoxic stress, prophase-arrested oocytes are highly capable of functionally efficient DNA repair. These data implicate DNA repair as a key quality control mechanism in the female germ line and a critical determinant of fertility and genetic integrity.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2001124117</identifier><identifier>PMID: 32381741</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Apoptosis ; Ataxia ; Ataxia telangiectasia ; Ataxia telangiectasia mutated protein ; Biological Sciences ; Damage localization ; Deoxyribonucleic acid ; DNA ; DNA damage ; DNA repair ; Fertility ; Gametocytes ; Genotoxicity ; Histone H2A ; Homologous recombination ; Homologous recombination repair ; Homology ; Integrity ; Irradiation ; Meiosis ; Offspring ; Oocytes ; Ovaries ; Prophase ; Quality control ; Radiation ; Repair</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2020-05, Vol.117 (21), p.11513-11522</ispartof><rights>Copyright National Academy of Sciences May 26, 2020</rights><rights>2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c509t-c6b0911af912db287dce36a87b143406c4d130e8415a9a9409ad7a48106e6bc13</citedby><cites>FETCH-LOGICAL-c509t-c6b0911af912db287dce36a87b143406c4d130e8415a9a9409ad7a48106e6bc13</cites><orcidid>0000-0001-7848-1447 ; 0000-0001-6624-4698</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26930975$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26930975$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32381741$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Stringer, Jessica M.</creatorcontrib><creatorcontrib>Winship, Amy</creatorcontrib><creatorcontrib>Zerafa, Nadeen</creatorcontrib><creatorcontrib>Wakefield, Matthew</creatorcontrib><creatorcontrib>Hutt, Karla</creatorcontrib><title>Oocytes can efficiently repair DNA double-strand breaks to restore genetic integrity and protect offspring health</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Female fertility and offspring health are critically dependent on an adequate supply of high-quality oocytes, the majority of which are maintained in the ovaries in a unique state of meiotic prophase arrest. While mechanisms of DNA repair during meiotic recombination are well characterized, the same is not true for prophase-arrested oocytes. Here we show that prophase-arrested oocytes rapidly respond to γ-irradiation–induced DNA double-strand breaks by activating Ataxia Telangiectasia Mutated, phosphorylating histone H2AX, and localizing RAD51 to the sites of DNA damage. Despite mobilizing the DNA repair response, even very low levels of DNA damage result in the apoptosis of prophase-arrested oocytes. However, we show that, when apoptosis is inhibited, severe DNA damage is corrected via homologous recombination repair. The repair is sufficient to support fertility and maintain health and genetic fidelity in offspring. Thus, despite the preferential induction of apoptosis following exogenously induced genotoxic stress, prophase-arrested oocytes are highly capable of functionally efficient DNA repair. These data implicate DNA repair as a key quality control mechanism in the female germ line and a critical determinant of fertility and genetic integrity.</description><subject>Apoptosis</subject><subject>Ataxia</subject><subject>Ataxia telangiectasia</subject><subject>Ataxia telangiectasia mutated protein</subject><subject>Biological Sciences</subject><subject>Damage localization</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA repair</subject><subject>Fertility</subject><subject>Gametocytes</subject><subject>Genotoxicity</subject><subject>Histone H2A</subject><subject>Homologous recombination</subject><subject>Homologous recombination repair</subject><subject>Homology</subject><subject>Integrity</subject><subject>Irradiation</subject><subject>Meiosis</subject><subject>Offspring</subject><subject>Oocytes</subject><subject>Ovaries</subject><subject>Prophase</subject><subject>Quality control</subject><subject>Radiation</subject><subject>Repair</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNpdkUtv1DAUhSMEotPCmhXIEptu0l4_EscbpKo8pYpuYG05zs2Mh4w9tR2k-fc4mjI8Vndxv3N0jk5VvaJwRUHy67036YoBUMoEpfJJtaKgaN0KBU-rFQCTdSeYOKvOU9oCgGo6eF6dccY7KgVdVQ_3wR4yJmKNJziOzjr0eTqQiHvjInn_9YYMYe4nrFOOxg-kj2h-JJJDQVIOEckaPWZnifMZ19HlA1m4fQwZbSZhHNM-Or8mGzRT3ryono1mSvjy8V5U3z9--Hb7ub67__Tl9uautg2oXNu2L02oGRVlQ886OVjkrelkTwUX0FoxUA7YCdoYZZQAZQZpREehxba3lF9U746--7nfYVH7kn_SJcrOxIMOxul_P95t9Dr81JK1oBQUg8tHgxge5tJV71yyOE3GY5iTZgKg4Z3s2oK-_Q_dhjn6Um-hJBesaWShro-UjSGliOMpDAW9zKmXOfWfOYvizd8dTvzv_Qrw-ghslylOf9YqDko2_BcKcKcK</recordid><startdate>20200526</startdate><enddate>20200526</enddate><creator>Stringer, Jessica M.</creator><creator>Winship, Amy</creator><creator>Zerafa, Nadeen</creator><creator>Wakefield, Matthew</creator><creator>Hutt, Karla</creator><general>National Academy of Sciences</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-7848-1447</orcidid><orcidid>https://orcid.org/0000-0001-6624-4698</orcidid></search><sort><creationdate>20200526</creationdate><title>Oocytes can efficiently repair DNA double-strand breaks to restore genetic integrity and protect offspring health</title><author>Stringer, Jessica M. ; Winship, Amy ; Zerafa, Nadeen ; Wakefield, Matthew ; Hutt, Karla</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c509t-c6b0911af912db287dce36a87b143406c4d130e8415a9a9409ad7a48106e6bc13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Apoptosis</topic><topic>Ataxia</topic><topic>Ataxia telangiectasia</topic><topic>Ataxia telangiectasia mutated protein</topic><topic>Biological Sciences</topic><topic>Damage localization</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA damage</topic><topic>DNA repair</topic><topic>Fertility</topic><topic>Gametocytes</topic><topic>Genotoxicity</topic><topic>Histone H2A</topic><topic>Homologous recombination</topic><topic>Homologous recombination repair</topic><topic>Homology</topic><topic>Integrity</topic><topic>Irradiation</topic><topic>Meiosis</topic><topic>Offspring</topic><topic>Oocytes</topic><topic>Ovaries</topic><topic>Prophase</topic><topic>Quality control</topic><topic>Radiation</topic><topic>Repair</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Stringer, Jessica M.</creatorcontrib><creatorcontrib>Winship, Amy</creatorcontrib><creatorcontrib>Zerafa, Nadeen</creatorcontrib><creatorcontrib>Wakefield, Matthew</creatorcontrib><creatorcontrib>Hutt, Karla</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</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>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Stringer, Jessica M.</au><au>Winship, Amy</au><au>Zerafa, Nadeen</au><au>Wakefield, Matthew</au><au>Hutt, Karla</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Oocytes can efficiently repair DNA double-strand breaks to restore genetic integrity and protect offspring health</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2020-05-26</date><risdate>2020</risdate><volume>117</volume><issue>21</issue><spage>11513</spage><epage>11522</epage><pages>11513-11522</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Female fertility and offspring health are critically dependent on an adequate supply of high-quality oocytes, the majority of which are maintained in the ovaries in a unique state of meiotic prophase arrest. While mechanisms of DNA repair during meiotic recombination are well characterized, the same is not true for prophase-arrested oocytes. Here we show that prophase-arrested oocytes rapidly respond to γ-irradiation–induced DNA double-strand breaks by activating Ataxia Telangiectasia Mutated, phosphorylating histone H2AX, and localizing RAD51 to the sites of DNA damage. Despite mobilizing the DNA repair response, even very low levels of DNA damage result in the apoptosis of prophase-arrested oocytes. However, we show that, when apoptosis is inhibited, severe DNA damage is corrected via homologous recombination repair. The repair is sufficient to support fertility and maintain health and genetic fidelity in offspring. Thus, despite the preferential induction of apoptosis following exogenously induced genotoxic stress, prophase-arrested oocytes are highly capable of functionally efficient DNA repair. These data implicate DNA repair as a key quality control mechanism in the female germ line and a critical determinant of fertility and genetic integrity.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>32381741</pmid><doi>10.1073/pnas.2001124117</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0001-7848-1447</orcidid><orcidid>https://orcid.org/0000-0001-6624-4698</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0027-8424 |
| ispartof | Proceedings of the National Academy of Sciences - PNAS, 2020-05, Vol.117 (21), p.11513-11522 |
| issn | 0027-8424 1091-6490 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7260990 |
| source | PubMed Central (Open Access); Alma/SFX Local Collection; Free Full-Text Journals in Chemistry; JSTOR |
| subjects | Apoptosis Ataxia Ataxia telangiectasia Ataxia telangiectasia mutated protein Biological Sciences Damage localization Deoxyribonucleic acid DNA DNA damage DNA repair Fertility Gametocytes Genotoxicity Histone H2A Homologous recombination Homologous recombination repair Homology Integrity Irradiation Meiosis Offspring Oocytes Ovaries Prophase Quality control Radiation Repair |
| title | Oocytes can efficiently repair DNA double-strand breaks to restore genetic integrity and protect offspring health |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-01T06%3A42%3A21IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-jstor_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Oocytes%20can%20efficiently%20repair%20DNA%20double-strand%20breaks%20to%20restore%20genetic%20integrity%20and%20protect%20offspring%20health&rft.jtitle=Proceedings%20of%20the%20National%20Academy%20of%20Sciences%20-%20PNAS&rft.au=Stringer,%20Jessica%20M.&rft.date=2020-05-26&rft.volume=117&rft.issue=21&rft.spage=11513&rft.epage=11522&rft.pages=11513-11522&rft.issn=0027-8424&rft.eissn=1091-6490&rft_id=info:doi/10.1073/pnas.2001124117&rft_dat=%3Cjstor_pubme%3E26930975%3C/jstor_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2407342557&rft_id=info:pmid/32381741&rft_jstor_id=26930975&rfr_iscdi=true |