DIV-1/PolA2 Promotes GLP-1/Notch-Mediated Cellular Events in Caenorhabditis elegans

Abstract

Notch signaling is a highly conserved cell signaling system in most multicellular organisms and plays a critical role in animal development. In various tumor cells, Notch signaling is elevated and has been considered as an important target in cancer treatments. In C. elegans, GLP-1 (one of two C. elegans Notch receptors) activity is required for cell fate specification in germline and somatic tissues. In this study, we have identified div-1 gene as a positive regulator for GLP-1/Notch-mediated cellular events. C. elegans div-1 encodes the B subunit of the DNA polymerase alpha-primase complex and is highly expressed in proliferative germ cells. Functional analyses demonstrated that i) DIV-1 is required for the robust proliferation typical of the germline, ii) loss of DIV-1 enhances and suppresses specific phenotypes that are associated with reduced and elevated GLP-1/Notch activity in germline and somatic tissues, and iii) DIV-1 works together with FBF/PUF proteins, downstream regulators of GLP-1/Notch signaling, to promote germline stem cell (GSC) maintenance and germline proliferation. To maintain GSCs and proliferative cell fate, GLP-1/Notch activity must remain above a threshold for proliferation/differentiation decision. Our results propose that DIV-1 may control the level of threshold for GLP-1/Notch-mediated germline proliferation. PolA2, a mammalian homolog of the C. elegans DIV-1, has been emerged as a therapeutic target for non-small cell lung cancer (NSCLC). Notably, Notch signaling is altered in approximately one third of NSCLCs. Therefore, the discovery of the DIV-1 effect on GLP-1/Notch-mediated cellular events has implications for our understanding of vertebrate PolA2 protein and its influence on stem cell maintenance and tumorigenesis.