PDRG1at the interface between intermediary metabolism and oncogenesis

Abstract

PDRG1 is a small oncogenic protein of 133 residues. In normal human tissues, the p53 and DNA damage-regulated gene 1 (PDRG1) gene exhibits maximal expression in the testis and minimal levels in the liver. Increased expression has been detected in several tumor cells and in response to genotoxic stress. High-throughput studies identified the PDRG1 protein in a variety of macromolecular complexes involved in processes that are altered in cancer cells. For example, this oncogene has been found as part of the RNA polymerase II complex, the splicing machinery and nutrient sensing machinery, although its role in these complexes remains unclear. More recently, the PDRG1 protein was found as an interaction target for the catalytic subunits of methionine adenosyltransferases. These enzymes synthesize S-adenosylmethionine, the methyl donor for, among others, epigenetic methylations that occur on the DNA and histones. In fact, downregulation of S-adenosylmethionine synthesis is the first functional effect directly ascribed to PDRG1. The existence of global DNA hypomethylation, together with increased PDRG1 expression, in many tumor cells highlights the importance of this interaction as one of the putative underlying causes for cell transformation. Here, we will review the accumulated knowledge on this oncogene, emphasizing the numerous aspects that remain to be explored.

Protein-protein interactions involving enzymes of the mammalian methionine and homocysteine metabolism

“…3). Both proteins exhibit nucleocytoplasmic distribution [39,76], but coimmunoprecipitation only captured the complex (~360 kDa) in nuclear fractions [39]. Information derived from the construction of a structural homology model of the PDRG1 core (K27-Q106) using prefoldin helped to design truncated forms of the protein, which aided into the identification of the interaction site [39].…”

“…Information regarding PDRG1 is limited and mainly related to its isolation in several macromolecular complexes, including the RNA polymerase II, the U12-type spliceosome, the R2TP prefoldin complex, as well as others involved in chromatin remodeling (e.g. INO80) and nutrient sensing [76]. Colocalization of PDRG1 and MATa1 with the nuclear speckles marker SC-35 [12,39], further suggests their involvement in complexes such as the spliceosome.…”

“…Moreover, the PDRG1-MATa1 interaction may allow crosstalk of methionine metabolism with a variety of macromolecular complexes containing PDRG1 (Fig. 5) [76].…”

“…Subsequent PDRG1 interactions, or their preclusion by MATa binding, may modulate apoptosis, through the U12-type spliceosome protein PDCD7 [119], or RNA polymerase II assembly, through proteins included in the prefoldin complex (URI and are included [76,78,98], although in many cases these relationships can be only inferred.…”

Role of R2tp Complex in Lymphoma and Its Therapeutic Potential

“…More recently, this protein has been uncovered as an interaction target for methionine adenosyl-transferase catalytic subunits MATα1 and MATα2. Through this interaction, PDRG1 downregulates nuclear S-adenosylmethionine synthesis, hence impacting epigenetic methylations (18).RPAP3 isoform 1, but not isoform 2, interacts with PIH1D1 for its stabilization probably due to the protection from its degradation. Elucidation of the mechanism by which RPAP3 isoform 2 reduces the cell survival pathway may provide approaches for the treatment of cancer (19).…”