CHK1-CDC25A-CDK1 regulate cell cycle progression in early mouse embryos to protect genome integrity

Abstract

ABSTRACTAfter fertilization, remodeling of the oocyte and sperm genomes is essential to convert these highly differentiated non-dividing transcriptionally quiescent cells into early cleavage-stage transcriptionally active totipotent blastomeres. This developmental transition is accompanied by cell cycle adaptation such as lengthening or shortening of the gap phases G1 and G2. However, regulation of these cell cycle changes is poorly understood, especially in mammals. Checkpoint kinase 1 (CHK1) is a protein kinase that regulates cell cycle progression in somatic cells. Here, we show that CHK1 regulates cell cycle progression in early mouse embryos by restraining CDK1 kinase activity due to CDC25A phosphatase degradation. CHK1 kinase also ensures the long G2 phase needed for genome activation and reprogramming gene expression in 2-cell stage mouse embryos. Last,Chk1depletion leads to DNA damage and chromosome segregation errors that result in aneuploidy and infertility.