The cyclin-dependent kinase inhibitors, cki-1 and cki-2, act in overlapping but distinct pathways to control cell cycle quiescence during C. elegans development

Cyclin-dependent kinase inhibitors (CKIs) are major contributors to the decision to enter or exit the cell cycle. The Caenorhabditis elegans genome encodes two CKIs belonging to the Cip/Kip family, cki-1 and cki-2. cki-1 has been shown to act as a canonical negative regulator of cell cycle entry, while the role of cki-2 remains unclear. We identified cki-2 in a genome-wide RNAi screen to reveal genes essential for developmental cell cycle quiescence. Examination of cki-2 knockout animals revealed extra rounds of cell divisions, verifying a role in establishing or maintaining the temporary cell cycle arrest. Despite the overlapping defects, the pathways mediated by cki-1 and cki-2 are discrete since the extra cell phenotype conferred by a putative cki-2(null) mutation is enhanced upon additional loss of cki-1 activity. Moreover, the extra cell division defect of cki-2 is not increased with the additional loss of lin-35 Rb, as is seen with cki-1. Thus, both cki-1 and cki-2 mediate cell cycle quiescence, but our genetic and phenotypic analyses demonstrate that they act within distinct pathways to exert control over the cell cycle machinery.