Functional analysis of the unconventional prefoldin URI-1 in Caenorhabditis elegans

URI is a conserved unconventional member of the prefoldin family of molecular
chaperones that, at the biochemical and biological level, is multifunctional. It interacts with
several proteins with key roles in transcriptional control, including the RPB5 core subunit
of RNA pol II and the TIP49/TIP48 ATPases, components of various chromatinremodeling
complexes. More recently, URI has also been shown to interact with the
parathyroid tumor suppressor parafibromin, a component of the PAF1 complex involved in
histone methylation and cell cycle control. Notably, there is evidence from functional
studies in yeast and human cells that URI acts downstream of the target-of-rapamycin
(TOR) and the insulin-sensitive PI3K signaling pathways to control rapamycin-sensitive
transcriptional programs. Thus, it appears that URI participates in signaling circuits
dedicated, at least in part, to the integration of diverse metabolic and hormonal cues to
control cell growth and division.
This thesis demonstrates that the uri-1 orthologue in C. elegans is highly expressed at the
mRNA and protein level in the germ line and is critically important for germ cell
proliferation. More specifically, we observed that URI-1-deficient cells arrest at
prometaphase of the mitotic division cycle and display DNA breakage, as evidenced by
TUNEL staining and the appearance of HUS-1::GFP foci formation, implying that one or
more functions of URI-1 might be linked, directly or indirectly, to the suppression of DNA
damage and cell cycle arrest. Moreover, uri-1 +/- mutants or cells depleted of URI-1
function display an increased germ line apoptosis in the meiotic compartment. Notably, the
latter is a p53-dependent phenomenon, which in turn demonstrates that it is the result of
endogenous genotoxic DNA damage. These results, taken together, imply key roles for C.
elegans URI-1 in signaling circuits dedicated to genomic integrity control and the
suppression of cell cycle arrest and apoptosis.