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RPA, a single-stranded DNA-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\u2013stage 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 a previously unrecognized role in DNA damage repair during mammalian folliculogenesis.<\/jats:p>","DOI":"10.1093\/biolre\/ioag049","type":"journal-article","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T12:43:35Z","timestamp":1772023415000},"page":"1703-1717","source":"Crossref","is-referenced-by-count":0,"title":["Replication protein A1 is essential for DNA damage repair during mammalian oogenesis"],"prefix":"10.1093","volume":"114","author":[{"given":"Xiaosu","family":"Miao","sequence":"first","affiliation":[{"name":"Department of Veterinary and Animal Sciences, University of Massachusetts , Amherst, MA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine , Philadelphia, PA ,","place":["USA"]},{"name":"NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University , Hefei, Anhui ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Animal Sciences, University of Massachusetts , Amherst, MA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaylei","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Animal Sciences, University of Massachusetts , Amherst, MA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vienna","family":"Rivard","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Animal Sciences, University of Massachusetts , Amherst, MA ,","place":["USA"]},{"name":"Animal Models Core Facility, Institute for Applied Life Sciences (IALS), University of Massachusetts , Amherst, MA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Animal Sciences, University of Massachusetts , Amherst, MA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine , Philadelphia, PA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P Jeremy","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine , Philadelphia, PA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7281-3471","authenticated-orcid":false,"given":"Wei","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Animal Sciences, University of Massachusetts , Amherst, MA ,","place":["USA"]},{"name":"Animal Models Core Facility, Institute for Applied Life Sciences (IALS), University of Massachusetts , Amherst, MA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,3,6]]},"reference":[{"key":"2026051501265930900_ref1","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/0014-4827(61)90449-9","article-title":"Oogenesis in the mouse. 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