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DOI | 10.1038/nature24679 |
Female-biased embryonic death from inflammation induced by genomic instability | |
McNairn, Adrian J.1; Chuang, Chen-Hua2; Bloom, Jordana C.1; Wallace, Marsha D.3; Schimenti, John C.1,4 | |
2019-03-07 | |
发表期刊 | NATURE
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ISSN | 0028-0836 |
EISSN | 1476-4687 |
出版年 | 2019 |
卷号 | 567期号:7746页码:105-+ |
文章类型 | Article |
语种 | 英语 |
国家 | USA; England |
英文摘要 | 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 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 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. |
领域 | 地球科学 ; 气候变化 ; 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000460426900050 |
WOS关键词 | DNA-DAMAGE ; ANDROGEN RECEPTOR ; DORMANT ORIGINS ; EXCESS MCM2-7 ; HUMAN-CELLS ; REPLICATION ; INTERLEUKIN-10 |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/202825 |
专题 | 地球科学 资源环境科学 气候变化 |
作者单位 | 1.Cornell Univ, Coll Vet Med, Dept Biomed Sci, Ithaca, NY 14853 USA; 2.AbbVie, Redwood City, CA USA; 3.Univ London, Royal Vet Coll, Dept Clin Sci & Serv, Hatfield, Herts, England; 4.Cornell Univ, Cornell Ctr Vertebrate Genom, Ithaca, NY 14853 USA |
推荐引用方式 GB/T 7714 | McNairn, Adrian J.,Chuang, Chen-Hua,Bloom, Jordana C.,et al. Female-biased embryonic death from inflammation induced by genomic instability[J]. NATURE,2019,567(7746):105-+. |
APA | McNairn, Adrian J.,Chuang, Chen-Hua,Bloom, Jordana C.,Wallace, Marsha D.,&Schimenti, John C..(2019).Female-biased embryonic death from inflammation induced by genomic instability.NATURE,567(7746),105-+. |
MLA | McNairn, Adrian J.,et al."Female-biased embryonic death from inflammation induced by genomic instability".NATURE 567.7746(2019):105-+. |
条目包含的文件 | 条目无相关文件。 |
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