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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

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Transient inhibition of p53 homologs protects ovarian function from two distinct apoptotic pathways triggered by

So-Youn Kim1, Devi M Nair2, Megan Romero3

  • 1Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. so-youn-kim@northwestern.edu.

Cell Death and Differentiation
|July 11, 2018
PubMed

Insights

Platinum chemotherapy and radiation damage oocytes via distinct pathways. Inhibiting DNA damage response kinases fully preserves ovarian function and fertility in mice against both treatments.

Area of Science:

  • Reproductive biology
  • Molecular oncology
  • Cellular signaling

Background:

  • Platinum-based chemotherapies can cause ovarian insufficiency by reducing ovarian reserve.
  • Oocyte apoptosis is a key mechanism, potentially involving TAp63α phosphorylation by kinases like CHEK2, CK1, and ABL1.

Purpose of the Study:

  • To elucidate the novel pathway of cisplatin-induced oocyte apoptosis.
  • To investigate the feasibility of protecting ovarian function against chemotherapy and radiation.

Main Methods:

  • Investigated cisplatin (CDDP) and X-irradiation effects on oocyte apoptosis in vivo.
  • Utilized oocyte-specific gene deletion and kinase inhibitors targeting DNA damage response pathways (ATR/CHEK1, ATM/CHEK2).
  • Assessed TAp63α activation, phosphorylation, and overall ovarian function and fertility preservation.

Main Results:

  • CDDP induces oocyte apoptosis via the ATR > CHEK1 pathway, independent of TAp63α hyper-phosphorylation.
  • X-irradiation activates the ATM > CHEK2 > TAp63α hyper-phosphorylation pathway.
  • Temporary repression of DNA damage response kinases (ATM, ATR, CHEK1, CHEK2) fully preserves fertility in mice against both CDDP and X-ray.

Conclusions:

  • Established distinct molecular pathways for CDDP and X-ray-induced oocyte apoptosis.
  • Demonstrated that temporary inhibition of DNA damage response pathways is a viable strategy for preserving ovarian function against gonadotoxic agents.
  • Provides a molecular basis for developing adjuvant therapies to protect fertility.

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