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Replication Protein A1 is essential for DNA damage repair during mammalian oogenesis
Persistence of unrepaired DNA damage in oocytes is detrimental and may cause genetic aberrations, miscarriage, and infertility. RPA, an ssDNA-binding complex, is essential for various DNA-related processes. Here we report that RPA plays a novel role in DNA damage repair during postnatal oocyte devel...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10349974/ https://www.ncbi.nlm.nih.gov/pubmed/37461444 http://dx.doi.org/10.1101/2023.07.04.547725 |
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author | Miao, Xiaosu Guo, Rui Williams, Andrea Lee, Catherine Ma, Jun Wang, P. Jeremy Cui, Wei |
author_facet | Miao, Xiaosu Guo, Rui Williams, Andrea Lee, Catherine Ma, Jun Wang, P. Jeremy Cui, Wei |
author_sort | Miao, Xiaosu |
collection | PubMed |
description | Persistence of unrepaired DNA damage in oocytes is detrimental and may cause genetic aberrations, miscarriage, and infertility. RPA, an ssDNA-binding complex, is essential for various DNA-related processes. Here we report that RPA plays a novel role in DNA damage repair during postnatal oocyte development after meiotic recombination. To investigate the role of RPA during oogenesis, we inactivated RPA1 (replication protein A1), the largest subunit of the heterotrimeric RPA complex, specifically in oocytes using two germline-specific Cre drivers (Ddx4-Cre and Zp3-Cre). We find that depletion of RPA1 leads to the disassembly of the RPA complex, as evidenced by the absence of RPA2 and RPA3 in RPA1-deficient oocytes. Strikingly, severe DNA damage occurs in RPA1-deficient GV-stage oocytes. Loss of RPA in oocytes triggered the canonical DNA damage response mechanisms and pathways, such as activation of ATM, ATR, DNA-PK, and p53. In addition, the RPA deficiency causes chromosome misalignment at metaphase I and metaphase II stages of oocytes, which is consistent with altered transcript levels of genes involved in cytoskeleton organization in RPA1-deficient oocytes. Absence of the RPA complex in oocytes severely impairs folliculogenesis and leads to a significant reduction in oocyte number and female infertility. Our results demonstrate that RPA plays an unexpected role in DNA damage repair during mammalian folliculogenesis. |
format | Online Article Text |
id | pubmed-10349974 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-103499742023-07-17 Replication Protein A1 is essential for DNA damage repair during mammalian oogenesis Miao, Xiaosu Guo, Rui Williams, Andrea Lee, Catherine Ma, Jun Wang, P. Jeremy Cui, Wei bioRxiv Article Persistence of unrepaired DNA damage in oocytes is detrimental and may cause genetic aberrations, miscarriage, and infertility. RPA, an ssDNA-binding complex, is essential for various DNA-related processes. Here we report that RPA plays a novel role in DNA damage repair during postnatal oocyte development after meiotic recombination. To investigate the role of RPA during oogenesis, we inactivated RPA1 (replication protein A1), the largest subunit of the heterotrimeric RPA complex, specifically in oocytes using two germline-specific Cre drivers (Ddx4-Cre and Zp3-Cre). We find that depletion of RPA1 leads to the disassembly of the RPA complex, as evidenced by the absence of RPA2 and RPA3 in RPA1-deficient oocytes. Strikingly, severe DNA damage occurs in RPA1-deficient GV-stage oocytes. Loss of RPA in oocytes triggered the canonical DNA damage response mechanisms and pathways, such as activation of ATM, ATR, DNA-PK, and p53. In addition, the RPA deficiency causes chromosome misalignment at metaphase I and metaphase II stages of oocytes, which is consistent with altered transcript levels of genes involved in cytoskeleton organization in RPA1-deficient oocytes. Absence of the RPA complex in oocytes severely impairs folliculogenesis and leads to a significant reduction in oocyte number and female infertility. Our results demonstrate that RPA plays an unexpected role in DNA damage repair during mammalian folliculogenesis. Cold Spring Harbor Laboratory 2023-07-04 /pmc/articles/PMC10349974/ /pubmed/37461444 http://dx.doi.org/10.1101/2023.07.04.547725 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. |
spellingShingle | Article Miao, Xiaosu Guo, Rui Williams, Andrea Lee, Catherine Ma, Jun Wang, P. Jeremy Cui, Wei Replication Protein A1 is essential for DNA damage repair during mammalian oogenesis |
title | Replication Protein A1 is essential for DNA damage repair during mammalian oogenesis |
title_full | Replication Protein A1 is essential for DNA damage repair during mammalian oogenesis |
title_fullStr | Replication Protein A1 is essential for DNA damage repair during mammalian oogenesis |
title_full_unstemmed | Replication Protein A1 is essential for DNA damage repair during mammalian oogenesis |
title_short | Replication Protein A1 is essential for DNA damage repair during mammalian oogenesis |
title_sort | replication protein a1 is essential for dna damage repair during mammalian oogenesis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10349974/ https://www.ncbi.nlm.nih.gov/pubmed/37461444 http://dx.doi.org/10.1101/2023.07.04.547725 |
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