# The Role and Regulation of TRP53 Activity in Oocytes and Granulosa Cells After Radiation-induced Damage

> **NIH NIH F31** · JACKSON LABORATORY · 2022 · $32,986

## Abstract

Project Summary
Ionizing radiation (IR) is a treatment used against cancer and to ablate patient's bone marrow prior to
hematopoietic stem cell transplantation. IR induces damage (double strand breaks or reactive oxygen species)
in target cells but can also kill healthy bystander cells. Primordial follicles (PFs) are a limited population of ovarian
follicles that contain immature oocytes and are highly susceptible to damage. Damage induced by IR or other
genotoxic chemotherapies can deplete the ovary of PFs resulting in premature ovarian insufficiency (POI) and
infertility. Therefore, there is a need to understand how damage affects ovarian cells and leads to POI before
less toxic therapeutic or predictive treatments can be developed. The goal of this project is to determine the
mechanism of radiation-induced oocyte elimination in mammals. How PF's response to damage is largely
unknown beyond a few major players. Checkpoint kinase 2 (CHEK2) primarily activates the pro-apoptotic TRP63
TA isoform (TAp63) in response to damage. In contrast, somatic cells predominantly use another CHEK2 target
TRP53. Our lab showed Chek2-/- female mice receiving IR retained their PF reserve and produced healthy pups.
TAp63-/- females receiving low dose IR maintained PFs while Trp53-/- mice lost their PF reserve. Suggesting that
TRP53 is dispensable for apoptosis in oocytes. In treatments with higher IR dose or chemotherapies, TAp63-/-
females lose PF reserve while Chek2-/- females retain PF reserve. We predicted higher doses of IR and
chemotherapies cause more damage, which activates a TAp63-independent mechanism. Indeed, TAp63-/-
Trp53-/- double mutant females exposed to higher dose IR retained PF reserve suggesting TRP53 triggers
oocyte elimination when a certain threshold of damage is reached. Analysis of TRP53 protein expression after
high dose IR identified a unique form of TRP53 in purified oocytes and the absence of the typical ~53kDa protein,
detected in somatic cells. Based on these observations we hypothesize TRP53 activity in oocytes is regulated
by an oocyte-specific mechanism which either activates TRP53 or restricts its action until a specific threshold of
damage occurs. This proposal will utilize genetic approaches (chimeric reconstituted ovaries) and proteomic
approaches (mass spectrometry) to determine TRP53 regulation in response to ovarian damage. The aims of
this proposed research are to (1) determine whether TRP53-dependent PF loss is triggered intrinsically in the
oocyte or is due to damage signals from somatic granulosa cells to the oocyte and 2) determine how TRP53
activity is regulated in oocytes by identifying unique post-translational modifications and/or protein interactions
associated with TRP53-dependent PF loss. Defining oocyte-specific mechanisms regulating pro-apoptotic
TRP53 activity in response to damage will improve our understanding of the PF response to genotoxic agents
and provide targets for therapeutics to prevent oocyte loss,...

## Key facts

- **NIH application ID:** 10466123
- **Project number:** 1F31HD108973-01
- **Recipient organization:** JACKSON LABORATORY
- **Principal Investigator:** Monique L MIlls
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $32,986
- **Award type:** 1
- **Project period:** 2022-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10466123

## Citation

> US National Institutes of Health, RePORTER application 10466123, The Role and Regulation of TRP53 Activity in Oocytes and Granulosa Cells After Radiation-induced Damage (1F31HD108973-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10466123. Licensed CC0.

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