Female-biased embryonic death from inflammation induced by genomic instability

Adrian J. McNairn, Chen-Hua Chuang, Jordana C. Bloom, Marsha D. Wallace and John C. Schimenti ()
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Adrian J. McNairn: Cornell University
Chen-Hua Chuang: AbbVie
Jordana C. Bloom: Cornell University
Marsha D. Wallace: University of London
John C. Schimenti: Cornell University

Nature, 2019, vol. 567, issue 7746, 105-108

Abstract: Abstract Genomic instability can trigger cellular responses that include checkpoint activation, senescence and inflammation1,2. Although genomic instability has been extensively studied in cell culture and cancer paradigms, little is known about its effect during embryonic development, a period of rapid cellular proliferation. Here we report that mutations in the heterohexameric minichromosome maintenance complex—the DNA replicative helicase comprising MCM2 to MCM73,4—that cause genomic instability render female mouse embryos markedly more susceptible than males to embryonic lethality. This bias was not attributable to X chromosome-inactivation defects, differential replication licensing or X versus Y chromosome size, but rather to ‘maleness’—XX embryos could be rescued by transgene-mediated sex reversal or testosterone administration. The ability of exogenous or endogenous testosterone to protect embryos was related to its anti-inflammatory properties5. Ibuprofen, a non-steroidal anti-inflammatory drug, rescued female embryos that contained mutations in not only the Mcm genes but also the Fancm gene; similar to MCM mutants, Fancm mutant embryos have increased levels of genomic instability (measured as the number of cells with micronuclei) from compromised replication fork repair6. In addition, deficiency in the anti-inflammatory IL10 receptor was synthetically lethal with the Mcm4Chaos3 helicase mutant. Our experiments indicate that, during development, DNA damage associated with DNA replication induces inflammation that is preferentially lethal to female embryos, because male embryos are protected by high levels of intrinsic testosterone.

Date: 2019
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DOI: 10.1038/s41586-019-0936-6

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