TY - JOUR T1 - A small increase in <em>CHEK1</em> activity leads to the arrest of the first zygotic division in human JF - bioRxiv DO - 10.1101/2020.12.26.424381 SP - 2020.12.26.424381 AU - Beili Chen AU - Jianying Guo AU - Ting Wang AU - Qianhui Lee AU - Jia Ming AU - Fangfang Ding AU - Haitao Li AU - Zhiguo Zhang AU - Lin Li AU - Yunxia Cao AU - Jie Na Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/01/13/2020.12.26.424381.abstract N2 - The first mitotic division in mammalian zygotes is unique. The fertilized egg reactivates its cell cycle, and the maternal and paternal genomes start to reprogram to become totipotent. The first division is very sensitive to a range of perturbations, particularly the DNA damage, leading to the embryo's failure to enter the first mitosis. We discovered that a point mutation in the human CHEK1 gene resulted in an Arginine 442 to Glutamine change at the C-terminus of the CHEK1 protein. CHEK1 R442Q mutation caused the zygote to arrest just before the first division. Heterozygote individuals appeared to be healthy except that the female carriers are infertile. Expressing the corresponding mouse mutant Chk1 protein in zygotes also caused arrest before the first mitosis. Treating Chk1 R442Q mouse zygotes with low concentrations of CHEK1 inhibitor enabled the embryos to overcome the cell cycle arrest and resume normal development. Our results revealed an unexpected zygote mitotic checkpoint, which is extremely sensitive to the CHEK1 kinase activity. The fine-tuning of the DNA damage checkpoint permits the arrested one-cell embryos to overcome the first mitotic block and develop into healthy animals. These findings have important implications in assisted human reproduction.Competing Interest StatementThe authors have declared no competing interest. ER -