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Female-biased embryonic death from genomic instability-induced inflammation

View ORCID ProfileAdrian J. McNairn, Chen-Hua Chuang, View ORCID ProfileJordana C. Bloom, Marsha D. Wallace, View ORCID ProfileJohn C. Schimenti
doi: https://doi.org/10.1101/400820
Adrian J. McNairn
1Cornell University College of Veterinary Medicine, Dept. of Biomedical Sciences
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Chen-Hua Chuang
2AbbVie Inc, Redwood City, CA
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Jordana C. Bloom
1Cornell University College of Veterinary Medicine, Dept. of Biomedical Sciences
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Marsha D. Wallace
3University of Oxford.
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John C. Schimenti
1Cornell University College of Veterinary Medicine, Dept. of Biomedical Sciences
4Cornell Center for Vertebrate Genomics.
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  • For correspondence: jcs92@cornell.edu
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Abstract

Genomic instability (GIN) can trigger cellular responses including checkpoint activation, senescence, and inflammation. Though extensively studied in cell culture and cancer paradigms, little is known about the impact of GIN during embryonic development, a period of rapid cellular proliferation. We report that GIN-causing mutations in the MCM2-7 DNA replicative helicase render female mouse embryos to be dramatically more susceptible than males to embryonic lethality. This bias was not attributable to X-inactivation defects, differential replication licensing, or X vs Y chromosome size, but rather “maleness,” since XX embryos could be rescued by transgene-mediated sex reversal or testosterone (T) administration. The ability of exogenous or endogenous T to protect embryos was related to its anti-inflammatory properties. The NSAID ibuprofen rescued female embryos containing mutations not only in MCM genes but also Fancm, which have elevated GIN from compromised replication fork repair. Additionally, deficiency for the anti-inflammatory IL10 receptor was synthetically lethal with the GIN-causing Mcm4Chaos3 helicase mutant. Our experiments indicate that embryonic and maternal GIN arising from DNA replication-associated DNA damage induces embryonic inflammation likely via the cGAS-STING response, preferentially killing female embryos while male embryos are protected by high levels of intrinsic T.

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Posted August 27, 2018.
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Female-biased embryonic death from genomic instability-induced inflammation
Adrian J. McNairn, Chen-Hua Chuang, Jordana C. Bloom, Marsha D. Wallace, John C. Schimenti
bioRxiv 400820; doi: https://doi.org/10.1101/400820
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Female-biased embryonic death from genomic instability-induced inflammation
Adrian J. McNairn, Chen-Hua Chuang, Jordana C. Bloom, Marsha D. Wallace, John C. Schimenti
bioRxiv 400820; doi: https://doi.org/10.1101/400820

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