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BRCA1 represses DNA replication initiation through antagonizing estrogen signaling and maintains genome stability in parallel with WEE1-MCM2 signaling during pregnancy
Xiaoling Xu1; Eric Chen2; Lihua Mo1; Lei Zhang1,5; Fangyuan Shao1; Kai Miao1; Jianlin Liu1; Sek Man Su1; Monica Valecha1; Un In Chan1; Hongping Zheng2; Mark Chen2; Weiping Chen3; Qiang Chen1; Haiqing Fu4; Mirit I. Aladjem4; Yanzhen He5; Chu-Xia Deng1
2018-11-15
Source PublicationHuman molecular genetics
ISSN0964-6906
Abstract

The mammary gland undergoes fast cell proliferation during early pregnancy, yet the mechanism to ensure genome integrity during this highly proliferative stage is largely unknown. We show that pregnancy triggers replicative stresses leading to genetic instability in mice carrying a mammary specific disruption of breast cancer associated gene-1 (BRCA1). The fast cell proliferation was correlated with enhanced expression of most genes encoding replisomes, which are positively regulated by estrogen/ERα signaling but negatively regulated by BRCA1. Our further analysis revealed two parallel signaling pathways, which are mediated by ATR–CHK1 and WEE1–MCM2 and are responsible for regulating DNA replication checkpoint. Upon DNA damage, BRCA1 deficiency markedly enhances DNA replication initiation and preferably impairs DNA replication checkpoint mediated by ATR and CHK1. Meanwhile, DNA damage also activates WEE1–MCM2 signaling, which inhibits DNA replication initiation and enables BRCA1-deficient cells to avoid further genomic instability. Finally, we demonstrated that overriding this defense by WEE1 inhibition in combination with cisplatin, which causes DNA damage, serves as a promising therapeutic approach for killing BRCA1-deficient cancer cells.

DOIhttps://doi.org/10.1093/hmg/ddy398
Language英语
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Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorXiaoling Xu; Chu-Xia Deng
Affiliation1.Faculty of Health Sciences, University of Macau, Macau SAR, China
2.Genetics of Development and Disease Branch
3.Gene Expression Core, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892
4.Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
5.Department of Vascular Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
First Author AffilicationFaculty of Health Sciences
Corresponding Author AffilicationFaculty of Health Sciences
Recommended Citation
GB/T 7714
Xiaoling Xu,Eric Chen,Lihua Mo,et al. BRCA1 represses DNA replication initiation through antagonizing estrogen signaling and maintains genome stability in parallel with WEE1-MCM2 signaling during pregnancy[J]. Human molecular genetics,2018.
APA Xiaoling Xu.,Eric Chen.,Lihua Mo.,Lei Zhang.,Fangyuan Shao.,...&Chu-Xia Deng.(2018).BRCA1 represses DNA replication initiation through antagonizing estrogen signaling and maintains genome stability in parallel with WEE1-MCM2 signaling during pregnancy.Human molecular genetics.
MLA Xiaoling Xu,et al."BRCA1 represses DNA replication initiation through antagonizing estrogen signaling and maintains genome stability in parallel with WEE1-MCM2 signaling during pregnancy".Human molecular genetics (2018).
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