Single-cell and bulk transcriptional profiling of mouse ovaries reveals novel genes and pathways associated with DNA damage response in oocytes
Open accessPublished version of a preprint
Abstract
Abstract Immature oocytes enclosed in primordial follicles stored in female ovaries are under constant threat of DNA damage induced by endogenous and exogenous factors. Checkpoint kinase 2 (CHEK2) is a key mediator of the DNA damage response in all cells. Genetic studies have shown that CHEK2 and its downstream targets, p53 and TAp63, regulate primordial follicle elimination in response to DNA damage, however the mechanism leading to their demise is still poorly characterized. Single-cell and bulk RNA sequencing were used to determine the DNA damage response in wildtype and Chek2 -deficient ovaries. A low but oocyte-lethal dose of ionizing radiation induces a DNA damage response in ovarian cells that is solely dependent on CHEK2. DNA damage activates multiple ovarian response pathways related to apoptosis, p53, interferon signaling, inflammation, cell adhesion, and intercellular communication. These pathways are differentially employed by different ovarian cell types, with oocytes disproportionately affected by radiation. Novel genes and pathways are induced by radiation specifically in oocytes, shedding light on their sensitivity to DNA damage, and implicating a coordinated response between oocytes and pre-granulosa cells within the follicle. These findings provide a foundation for future studies on the specific mechanisms regulating oocyte survival in the context of aging, as well as therapeutic and environmental genotoxic exposures.
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Cites
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- Authors
- Mills, M., Emori, C., Kumar, P., Boucher, Z., George, J., & Bolcun-Filas, E.
- Affiliations
- Jackson Laboratory (US)
- Research Institute for Microbial Diseases, The University of Osaka (JP)
- The Jackson Laboratory for Genomic Medicine (US)
- Venue
- Developmental Biology
- Publisher
- Elsevier BV
- Published
- 2025-01
- Volume
- 517
- Pages
- 55-72
- ISSN
- 0012-1606 (ISSN-L)
- PMC
- PMC12403231
- OpenAlex
- W4402630212
- Cited by
- 12
- References
- 10
- Citations by year
- 2026: 7 · 2025: 5
- FWCI
- 4.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Developmental Biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion, cc-by)
- PubMed Central (submittedVersion, cc-by)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion, cc-by)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- V Foundation (V2017-019)
- University of Arizona Cancer Center (P30 CA034196)
- National Institutes of Health
- National Cancer Institute (P30CA034196)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Keywords
- DNA damage response, oocytes, primordial follicles, CHEK2, ionizing radiation, p53, TAp63, apoptosis, interferon signaling, TNF signaling, NF-κB, apical junctions, pregranulosa cells, oocyte survival, ovarian aging, mouse ovary
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