Characterization of the role of VRK-1 in the proliferative germ cells of Caenorhabditis elegans

Vaccinia related kinase 1 (VRK-1) is a conserved kinase critical for many processes in the cell cycle. Reduction of VRK-1 activity in the C. elegans germ line causes proliferation defects that increase in severity and begin during the third larval stage of development. Germline VRK-1 has a cell-cycle-dependent pattern of expression in almost every germ cell. Two candidate targets of VRK-1 regulation were investigated for their involvement in the phenotype of vrk-1 mutant germ cells: barrier-to-autointegration factor (baf-1) and C. elegans p53 (cep-1). BAF-1 and VRK-1 probably act in parallel to synergistically regulate chromatin morphology. In contrast, germ cell proliferation and morphology defects of the vrk-1 mutant are greatly rescued by the additional loss of CEP-1 activity, suggesting that VRK-1 may inhibit CEP-1 in the proliferative germ cells. CEP-1 activity is not elevated in a vrk-1 mutant background as a consequence of DNA damage, since the loss of checkpoint genes does not rescue defects of vrk-1 mutant gonads. Since ectopic CEP-1 activity cannot be attributed to the misregulation of DNA checkpoint genes, VRK-1 regulation of CEP-1 is likely to be direct. Being that known CEP-1 inhibitors do not function in mitotic germ cells, VRK-1 is the first regulator of CEP-1 activity identified to function in germ line stem cells. VRK-1 is likely to be a pivotal coordinator of multiple substrates which act collectively to encourage proliferation and maintain integrity of germ cells in C. elegans.