Campus Units

Animal Science

Document Type

Article

Publication Version

Accepted Manuscript

Publication Date

8-22-2019

Journal or Book Title

Biology of Reproduction

DOI

10.1093/biolre/ioz160

Abstract

Ataxia telangiectasia mutated (ATM) protein recognizes and repairs DNA double strand breaks (DSB) through activation of cell cycle checkpoints and DNA repair proteins. Atm gene mutations increase female reproductive cancer risk. Phosphoramide mustard (PM) induces ovarian DNA damage and destroys primordial follicles, and pharmacological ATM inhibition prevents PM-induced follicular depletion. Wild-type (WT) C57BL/6 or Atm+/− mice were dosed once intraperitoneally with sesame oil (95%) or PM (25 mg/kg) in the proestrus phase of the estrous cycle and ovaries harvested 3 days thereafter. Atm+/− mice spent ~ 25% more time in diestrus phase than WT. LC-MS/MS on ovarian protein was performed and bioinformatically analyzed. Relative to WT, Atm+/−mice had 64 and 243 proteins increased or decreased in abundance, respectively. In WT mice, PM increased 162 and decreased 20 proteins. In Atm+/−mice, 173 and 37 proteins were increased and decreased, respectively, by PM. Exportin-2 (XPO2) was localized to granulosa cells of all follicle stages and was 7.2-fold greater in Atm+/− than WT mice. Cytoplasmic FMR1-interacting protein 1 (CYFIP1) was 6.8-fold lower in Atm+/− mice and was located in the surface epithelium with apparent translocation to the ovarian medulla post-PM exposure. PM induced γH2AX, but fewer γH2AX positive foci were identified in Atm+/− ovaries. Similarly, cleaved caspase-3 was lower in the Atm+/− PM-treated, relative to WT mice. These findings support ATM involvement in ovarian DNA repair and suggest that ATM functions to regulate ovarian atresia.

Comments

This is a manuscript of an article published as Clark, Kendra L., and Aileen F. Keating. "Ataxia Telangiectasia Mutated coordinates the ovarian DNA repair and atresia-initiating response to phosphoramide mustard." Biology of Reproduction (2019). doi: 10.1093/biolre/ioz160. Posted with permission.

Copyright Owner

The Authors

Language

en

File Format

application/pdf

Available for download on Saturday, August 22, 2020

Published Version

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