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Ataxia Telangiectasia Mutated Coordinates the Ovarian DNA Repair and Atresia-Initiating Response to Phosphoramide Mustard Kendra L

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Ataxia Telangiectasia Mutated Coordinates the Ovarian DNA Repair and Atresia-Initiating Response to Phosphoramide Mustard Kendra L Animal Science Publications Animal Science 8-22-2019 Ataxia Telangiectasia Mutated coordinates the ovarian DNA repair and atresia-initiating response to phosphoramide mustard Kendra L. Clark Iowa State University, [email protected] Aileen F. Keating Iowa State University, [email protected] Follow this and additional works at: https://lib.dr.iastate.edu/ans_pubs Part of the Animal Experimentation and Research Commons, Animal Sciences Commons, Cellular and Molecular Physiology Commons, Computational Biology Commons, Genetics Commons, and the Molecular Genetics Commons The ompc lete bibliographic information for this item can be found at https://lib.dr.iastate.edu/ ans_pubs/497. For information on how to cite this item, please visit http://lib.dr.iastate.edu/ howtocite.html. This Article is brought to you for free and open access by the Animal Science at Iowa State University Digital Repository. It has been accepted for inclusion in Animal Science Publications by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Ataxia Telangiectasia Mutated coordinates the ovarian DNA repair and atresia-initiating response to phosphoramide mustard 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. Keywords DNA repair, ovary, ovotoxicity, oncofertility Disciplines Animal Experimentation and Research | Animal Sciences | Cellular and Molecular Physiology | Computational Biology | Genetics | Molecular Genetics 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. This article is available at Iowa State University Digital Repository: https://lib.dr.iastate.edu/ans_pubs/497 1 Title: Ataxia Telangiectasia Mutated coordinates the ovarian DNA repair and atresia- initiating response to phosphoramide mustard Downloaded from https://academic.oup.com/biolreprod/advance-article-abstract/doi/10.1093/biolre/ioz160/5552033 by Iowa State University user on 28 August 2019 Kendra L. Clark and Aileen F. Keating* Department of Animal Science – Iowa State University, Ames, Iowa 50011 Running title: Atm haploinsufficiency impacts the DNA damage response Summary sentence: DNA repair is coordinated by ovarian ATM Keywords: DNA repair, ovary, ovotoxicity, oncofertility *Corresponding author: Aileen F. Keating, 2356H Kildee Hall, Department of Animal Science, Iowa State University, Ames, Iowa 50011, Email: [email protected] This work was in part funded by the Bailey Career Development Award from Iowa State University (AFK). Disclosure statement: The authors have nothing to disclose. 2 Abstract Ataxia telangiectasia mutated (ATM) protein recognizes and repairs DNA double strand breaks Downloaded from https://academic.oup.com/biolreprod/advance-article-abstract/doi/10.1093/biolre/ioz160/5552033 by Iowa State University user on 28 August 2019 (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 H2AX, but fewer H2AX 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. 3 Introduction Downloaded from https://academic.oup.com/biolreprod/advance-article-abstract/doi/10.1093/biolre/ioz160/5552033 by Iowa State University user on 28 August 2019 The integrity of the genome is constantly insulted by endogenous and exogenous sources and an intrinsic response is needed to effectively repair any damaged DNA. Ataxia telangiectasia mutated (ATM) protein is a major orchestrator of DNA repair and activated ATM precipitates the cellular DNA damage repair response (DDR). The cell cycle is arrested, and the DNA damage is fixed, or the cell is triggered for apoptosis if beyond repair [1]. ATM acts as a sensor and transducer of DNA damage, phosphorylating several downstream targets after activation including histone 2AX (H2AX) [2], mediator of DNA damage checkpoint protein 1 (MDC1) [3], and breast cancer type 1 susceptibility protein (BRCA1) [4] for DNA repair; serine/threonine-protein kinase Chk2 (CHK2) for cell cycle arrest [5]. After the repair process, ATM influences cellular fate by targeting p53 [6] for apoptosis, and RAC-alpha serine/threonine-protein kinase (AKT) [7] for cell survival. Elevated ATM is associated with a poor tumor response to chemotherapy and platinum resistance [8]. Mutations in Atm cause ataxia-telangiectasia (A-T) syndrome, a rare autosomal recessive disease characterized by neurodegeneration, immunodeficiency, increased radiosensitivity, cancer predisposition, and infertility [9]. A-T women have hypoplastic ovaries devoid of primordial follicles [10] and female Atm-/- mice are infertile and lack viable oocytes [11]. Women who are heterozygous carriers of mutated Atm have elevated cancer risk, particularly breast and ovarian [12-17], thus, receive anti-cancer therapy; a scenario that further increases their infertility risks. Cyclophosphamide (CPA) is an alkylating agent used in the treatment of cancers [18] and autoimmune disorders [19, 20] in adults and children. Phosphoramide mustard (PM), an 4 ovotoxic metabolite of CPA [21, 22], destroys rapidly dividing cells by inducing DNA double strand breaks (DSB) [23]. The reproductive effects of PM exposure have been well Downloaded from https://academic.oup.com/biolreprod/advance-article-abstract/doi/10.1093/biolre/ioz160/5552033 by Iowa State University user on 28 August 2019 characterized by our group and others, which include loss of primordial and primary follicles in mice [24-27], antral follicles in rats [28], and amenorrhea, premature ovarian failure, and infertility in women and young girls [29]. In addition to fertility issues, CPA exposure has been associated with congenital malformations in offspring exposed to CPA in utero as well as pre- gestational germ cell exposures [30]. Increasing cancer survival rates present the need to identify the mechanisms by which cancer therapies or other chemical exposures cause ovarian damage. ATM induction is the earliest observed event during PM-induced ovotoxicity and our group made the surprising observation that pharmacological inhibition of ATM prevents PM- induced follicular depletion ex vivo [31]. Thus, the hypothesis under investigation in this study was that the DNA damage response would be blunted in Atm+/- deficient mice and unhealthy follicles that normally would be triggered for repair and/or apoptosis would remain in the ovary. Our specific objectives were to determine if lowered ATM abundance affected PM-induced follicle loss and to investigate abundance and localization of ovarian DNA
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