PAR-5 is a PARty hub in the germline: Multitask proteins in development and disease.

As our understanding of how molecular machineries work expands, an increasing number of proteins that appear as regulators of different processes have been identified. These proteins are hubs within and among functional networks. The 14-3-3 protein family is involved in multiple cellular pathways and, therefore, influences signaling in several disease processes, from neurobiological disorders to cancer. As a consequence, 14-3-3 proteins are currently being investigated as therapeutic targets. Moreover, 14-3-3 protein levels have been associated with resistance to chemotherapies. There are seven 14-3-3 genes in humans, while Caenorhabditis elegans only possesses two, namely par-5 and ftt-2. Among the C. elegans scientific community, par-5 is mainly recognized as one of the par genes that is essential for the asymmetric first cell division in the embryo. However, a recent study from our laboratory describes roles of par-5 in germ cell proliferation and in the cellular response to DNA damage induced by genotoxic agents. In this review, we explore the broad functionality of 14-3-3 proteins in C. elegans and comment on the potential use of worms for launching a drugs/modifiers discovery platform for the therapeutic regulation of 14-3-3 function in cancer.

The 14-3-3 gene par-5 is required for germline development and DNA damage response in Caenorhabditis elegans.

14-3-3 proteins have been extensively studied in organisms ranging from yeast to mammals and are associated with multiple roles, including fundamental processes such as the cell cycle, apoptosis and the stress response, to diseases such as cancer. In Caenorhabditis elegans, there are two 14-3-3 genes, ftt-2 and par-5. ftt-2 is expressed only in somatic lineages, whereas par-5 expression is detected in both soma and germline. During early embryonic development, par-5 is necessary to establish cell polarity. 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 used a par-5 mutation and RNA interference to characterize par-5 functions in the germline. The lack of par-5 in germ cells caused cell cycle deregulation, the accumulation of endogenous DNA damage and genomic instability. Moreover, par-5 was required for checkpoint-induced cell cycle arrest in response to DNA-damaging agents. We propose a model in which PAR-5 regulates CDK-1 phosphorylation to prevent premature mitotic entry. This study opens a new path to investigate the mechanisms of 14-3-3 functions, which are not only essential for C. elegans development, but have also been shown to be altered in human diseases.