Cell cycle checkpoints in Caenorhabditis elegansthe 14-3-3 gene par-5 is required for germline development and DNA damage response / Checkpoints del ciclo celular en Caenorhabditis elegans: el gen 14-3-3, par-5, es necesario para el desarrollo y respuesta al daño genómico de la línea germinal

Resumen

14-3-3 proteins have been extensively studied from yeast to mammals, and are associated with multiple roles ranging from fundamental processes such as cell cycle, apoptosis and stress response to diseases such as neurodegeneration and cancer. Indeed, 14-3-3 proteins have been suggested as possible therapeutic targets in cancer treatment. There are seven 14-3-3 genes in mammals, whereas there are only two in Caenorhabditis elegans, ftt-2 and par-5. The ftt-2 gene is expressed only in somatic lineages, whereas par-5 expression is detected in both soma and germline. Although it is known that par-5 inactivation results in sterility, the role of this gene in germline development is poorly characterized. In the present study, we use a par-5 mutation and RNA interference to characterize par-5 functions in the germline. The lack of par-5 in germ cells causes cell cycle deregulation, the accumulation of endogenous DNA damage and genomic instability. Moreover, par-5 is required for checkpoint-induced cell cycle arrest in response to DNA-damaging agents. We propose a model whereby PAR-5 regulates CDK-1 phosphorylation to prevent premature mitotic entry. Even though mammalian 14-3-3 homologs have diverged into seven genes, we verified that the basic functions of 14-3-3 in cell cycle control have been conserved in C. elegans. Therefore, this study opens a new path to investigate molecular mechanisms of 14-3-3 proteins and establishes C. elegans as a suitable system to screen for genes (RNAi libraries or mutagenesis), and drugs which can modify 14-3-3 functions.