Details

Autor(en) / Beteiligte

• McNairn, Adrian J.
• Chuang, Chen-Hua
• Bloom, Jordana C.
• Wallace, Marsha D.
• Schimenti, John C.

Titel

Female-biased embryonic death from inflammation induced by genomic instability

Ist Teil von

• Nature (London), 2019-03, Vol.567 (7746), p.105-108

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• Genomic instability can trigger cellular responses that include checkpoint activation, senescence and inflammation 1 , 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 MCM7 3 , 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 properties 5 . 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 repair 6 . In addition, deficiency in the anti-inflammatory IL10 receptor was synthetically lethal with the Mcm4 Chaos3 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. Genomic instability, caused by MCM mutations, results in embryonic lethality that disproportionally affects female mouse embryos and is rescued by testosterone or ibuprofen treatment, both of which ameliorate inflammatory effects.