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| Status |
Public on Jan 21, 2025 |
| Title |
Replication Protein A1 is essential for DNA damage repair during mammalian oogenesis |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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 germinal vesicle (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.
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| Overall design |
Fully grown germinal vesicle (GV) oocytes were collected from PMSG-primed 4- to 5-week-old Control mice and Rpa1 oocyte-specific conditional knockout (OcKO) mice. Three biological replicates were prepared for each genotype (Control samples: 13, 14, 15; Rpa1 OcKO samples: 16, 17, 18) and each sample contained around 20 GV oocytes without any cumulus cells.
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| Contributor(s) |
Cui W |
| Citation missing |
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| Submission date |
Jan 16, 2025 |
| Last update date |
Jan 21, 2025 |
| Contact name |
Wei Cui |
| E-mail(s) |
wcui@umass.edu
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| Phone |
413-545-0673
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| Organization name |
University of Massachusetts Amherst
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| Street address |
240 Thatcher Road
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| City |
Amherst |
| State/province |
Massachusetts |
| ZIP/Postal code |
01003 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA1211671 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE287236_RAW.tar |
20.0 Mb |
(http)(custom) |
TAR (of TXT) |
| GSE287236_raw_counts.csv.gz |
655.1 Kb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
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