Enhancing survival of mouse oocytes following chemotherapy or aging by targeting Bax and Rad51.

<h4>Background</h4>Therapeutic approaches to preserve fertility in females undergoing cancer treatments are currently ineffective. This is partly due to limited knowledge of the molecular mechanisms that injured germ cells elicit to repair damage and survive or to abort repair and activa...

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Autores principales:	Loro L Kujjo, Tiina Laine, Ricardo J G Pereira, Wataru Kagawa, Hitoshi Kurumizaka, Shigeyuki Yokoyama, Gloria I Perez
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e5d0c4439ed54811ad6deffd2d32de33
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spelling	oai:doaj.org-article:e5d0c4439ed54811ad6deffd2d32de332021-11-25T06:25:53ZEnhancing survival of mouse oocytes following chemotherapy or aging by targeting Bax and Rad51.1932-620310.1371/journal.pone.0009204https://doaj.org/article/e5d0c4439ed54811ad6deffd2d32de332010-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20169201/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Therapeutic approaches to preserve fertility in females undergoing cancer treatments are currently ineffective. This is partly due to limited knowledge of the molecular mechanisms that injured germ cells elicit to repair damage and survive or to abort repair and activate biochemical pathways leading to death. So far, we know that following spontaneously occurring or drug-induced DNA damage, the efficiency of DNA repair is a critical determinant of the cell's fate. The protein encoded by the Rad51 gene is one of several components recruited for homologous recombination-dependent DNA double-strand break repair in both somatic cells and germ cells. Recently, we showed that microinjection of recombinant Rad51 into AKR/J mouse oocytes decreased the extent of spontaneous DNA double-strand breaks, suppressed apoptosis, and restored the developmental competence in AKR/J embryos. Herein we characterized the nature of chemotherapy-induced lesions in oocytes, and the associated individual components of the DNA damage sensor and repair apparatus. For comparison, we also assessed parallel spontaneous changes in aging oocytes.<h4>Methods</h4>Data collected were derived from: analysis of apoptosis; immunodepletion; oocyte microinjections; immunocytochemistry; immunofluorescence; and CHIP-like assays.<h4>Results</h4>Our data show that: (i) DNA damage in oocytes can be induced by both chemotherapy and spontaneously by the aging process; (ii) oocytes possess the machinery and capability for repairing such DNA damage; (iii) Rad51 is a critical player in the repair of both chemotherapy-induced and spontaneously-sustained DNA damage; and (iv) in response to damage, oocytes exhibit an inverse functional relationship between presence of Bax and activity of Rad51.<h4>Conclusion/significance</h4>Our results establish Rad51 and/or Bax as potential candidates that can be targeted for development of individualized chemotherapeutic interventions that are effective, but minimal in toxicity. The use of Rad51 and Bax modulating compounds could offer women the opportunity to maintain fully functional germ cells despite cancer treatments or aging.Loro L KujjoTiina LaineRicardo J G PereiraWataru KagawaHitoshi KurumizakaShigeyuki YokoyamaGloria I PerezPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 2, p e9204 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Loro L Kujjo Tiina Laine Ricardo J G Pereira Wataru Kagawa Hitoshi Kurumizaka Shigeyuki Yokoyama Gloria I Perez Enhancing survival of mouse oocytes following chemotherapy or aging by targeting Bax and Rad51.
description	<h4>Background</h4>Therapeutic approaches to preserve fertility in females undergoing cancer treatments are currently ineffective. This is partly due to limited knowledge of the molecular mechanisms that injured germ cells elicit to repair damage and survive or to abort repair and activate biochemical pathways leading to death. So far, we know that following spontaneously occurring or drug-induced DNA damage, the efficiency of DNA repair is a critical determinant of the cell's fate. The protein encoded by the Rad51 gene is one of several components recruited for homologous recombination-dependent DNA double-strand break repair in both somatic cells and germ cells. Recently, we showed that microinjection of recombinant Rad51 into AKR/J mouse oocytes decreased the extent of spontaneous DNA double-strand breaks, suppressed apoptosis, and restored the developmental competence in AKR/J embryos. Herein we characterized the nature of chemotherapy-induced lesions in oocytes, and the associated individual components of the DNA damage sensor and repair apparatus. For comparison, we also assessed parallel spontaneous changes in aging oocytes.<h4>Methods</h4>Data collected were derived from: analysis of apoptosis; immunodepletion; oocyte microinjections; immunocytochemistry; immunofluorescence; and CHIP-like assays.<h4>Results</h4>Our data show that: (i) DNA damage in oocytes can be induced by both chemotherapy and spontaneously by the aging process; (ii) oocytes possess the machinery and capability for repairing such DNA damage; (iii) Rad51 is a critical player in the repair of both chemotherapy-induced and spontaneously-sustained DNA damage; and (iv) in response to damage, oocytes exhibit an inverse functional relationship between presence of Bax and activity of Rad51.<h4>Conclusion/significance</h4>Our results establish Rad51 and/or Bax as potential candidates that can be targeted for development of individualized chemotherapeutic interventions that are effective, but minimal in toxicity. The use of Rad51 and Bax modulating compounds could offer women the opportunity to maintain fully functional germ cells despite cancer treatments or aging.
format	article
author	Loro L Kujjo Tiina Laine Ricardo J G Pereira Wataru Kagawa Hitoshi Kurumizaka Shigeyuki Yokoyama Gloria I Perez
author_facet	Loro L Kujjo Tiina Laine Ricardo J G Pereira Wataru Kagawa Hitoshi Kurumizaka Shigeyuki Yokoyama Gloria I Perez
author_sort	Loro L Kujjo
title	Enhancing survival of mouse oocytes following chemotherapy or aging by targeting Bax and Rad51.
title_short	Enhancing survival of mouse oocytes following chemotherapy or aging by targeting Bax and Rad51.
title_full	Enhancing survival of mouse oocytes following chemotherapy or aging by targeting Bax and Rad51.
title_fullStr	Enhancing survival of mouse oocytes following chemotherapy or aging by targeting Bax and Rad51.
title_full_unstemmed	Enhancing survival of mouse oocytes following chemotherapy or aging by targeting Bax and Rad51.
title_sort	enhancing survival of mouse oocytes following chemotherapy or aging by targeting bax and rad51.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/e5d0c4439ed54811ad6deffd2d32de33
work_keys_str_mv	AT lorolkujjo enhancingsurvivalofmouseoocytesfollowingchemotherapyoragingbytargetingbaxandrad51 AT tiinalaine enhancingsurvivalofmouseoocytesfollowingchemotherapyoragingbytargetingbaxandrad51 AT ricardojgpereira enhancingsurvivalofmouseoocytesfollowingchemotherapyoragingbytargetingbaxandrad51 AT watarukagawa enhancingsurvivalofmouseoocytesfollowingchemotherapyoragingbytargetingbaxandrad51 AT hitoshikurumizaka enhancingsurvivalofmouseoocytesfollowingchemotherapyoragingbytargetingbaxandrad51 AT shigeyukiyokoyama enhancingsurvivalofmouseoocytesfollowingchemotherapyoragingbytargetingbaxandrad51 AT gloriaiperez enhancingsurvivalofmouseoocytesfollowingchemotherapyoragingbytargetingbaxandrad51
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Enhancing survival of mouse oocytes following chemotherapy or aging by targeting Bax and Rad51.

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