BRCA1 Represses DNA Replication Fork Firing and Prevents Mitotic Catastrophe through Antagonizing Estrogen Signaling during Pregnancy

The mammary gland at early stages of pregnancy undergoes fast cell proliferation, yet the mechanism to ensure its genome integrity is largely unknown. Here we show that pregnancy enhances expression of genes involved in numerous pathways, including most genes encoding replisomes. In mouse mammary glands, replisome genes are positively regulated by estrogen/ERa signaling but negatively regulated by BRCA1. Upon DNA damage, BRCA1 deficiency markedly enhances DNA replication initiation. BRCA1 deficiency also preferably impairs DNA replication checkpoints mediated by ATR and CHK1 but not by WEE1, which inhibits DNA replication initiation through CDC7-MCM2 pathway and enables BRCA1-deficient cells to avoid further genomic instability. Thus, BRCA1 and WEE1 inhibit DNA replication initiation in a parallel manner to ensure genome stability for mammary gland development during pregnancy.

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Xu X, Chen E, Mo L, Zhang L, Shao F, Miao K, Liu J, Su SM, Valecha M, In Chan U, Zheng H, Chen M, Chen W, Chen Q, Fu H, Aladjem MI, He Y, Deng CX