Female-biased embryonic death from inflammation induced by genomic instability

Nature
Adrian J McNairnJohn C Schimenti

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 micronucl...Continue Reading

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Citations

Sep 11, 2019·Biology of Reproduction·Christian Lee AndersenXiaoqin Ye
Jul 16, 2019·Cellular and Molecular Life Sciences : CMLS·Sandra Segura-Bayona, Travis H Stracker
Jul 2, 2020·OncoTargets and Therapy·Shanbao LiJunming Xu
Jul 19, 2019·International Journal of Molecular Sciences·Katherine R Knox-ConcepcionLubo Zhang
Apr 21, 2020·OncoTargets and Therapy·Masae YooMasahide Ohmichi
Mar 3, 2019·Nature·Sarah Lambert
Aug 1, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Rossella TricaricoErica A Golemis
Nov 14, 2020·Genes & Development·Jordana C Bloom, John C Schimenti
Feb 22, 2021·Current Opinion in Cell Biology·Ksenia KrupinaDon W Cleveland
Aug 2, 2020·Trends in Genetics : TIG·Sara Carmela CredendinoIrene Cantone
Jul 13, 2021·Frontiers in Cell and Developmental Biology·Hervé Técher, Philippe Pasero
Aug 7, 2021·DNA Repair·Mumingjiang Munisha, John C Schimenti
Nov 12, 2021·Nucleic Acids Research·Mitsunori HigaMasatoshi Fujita

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Methods Mentioned

BETA
gene trap
PCR
RNA-seq
gene-trap
genotyping
transgenic
fluorescence-activated cell sorting
flow cytometry

Software Mentioned

Cufflinks
TopHat
cutadapt
ImageStudio
Fiji

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