CHK1‐CDC25A‐CDK1 regulate cell cycle progression and protect genome integrity in early mouse embryos

Abstract

After fertilization, remodeling of the oocyte and sperm genomes is essential to convert these highly differentiated and transcriptionally quiescent cells into early cleavage‐stage blastomeres that are transcriptionally active and totipotent. 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 two‐cell stage mouse embryos. Finally, Chk1 depletion leads to DNA damage and chromosome segregation errors that result in aneuploidy and infertility.

Collective effects of cell cleavage dynamics

“…Furthermore, the DNA damage checkpoint kinase Chk1 can negatively regulate Cdk1-CyclinB activity through Wee1, Cdc25 and through CyclinB translocation (Royou et al, 2008;Patil et al, 2013) (Figure 2A, inset). Cdk1, Cdc25 and Chk1 have been experimentally shown to regulate early embryonic cycles during Xenopus, zebrafish, Drosophila melanogaster and mouse development (Pomerening et al, 2003;Dalle Nogare et al, 2009;Trunnell et al, 2011;Chang and Ferrell, 2013;Zhang et al, 2014;Knoblochova et al, 2023). The mechanisms below describe how cell cycle lengthening is achieved in vivo by developmentally regulating the components of this universal cell cycle machinery within each cell (Figure 2).…”