Abstract
Human Polynucleotide Phosphorylase (hPNPaseold-35 or PNPT1) is an evolutionarily conserved 3′→5′ exoribonuclease implicated in the regulation of numerous physiological processes including maintenance of mitochondrial homeostasis, mtRNA import and aging-associated inflammation. From an RNase perspective, little is known about the RNA or miRNA species it targets for degradation or whose expression it regulates; except for c-myc and miR-221. To further elucidate the functional implications of hPNPaseold-35 in cellular physiology, we knocked-down and overexpressed hPNPaseold-35 in human melanoma cells and performed gene expression analyses to identify differentially expressed transcripts. Ingenuity Pathway Analysis indicated that knockdown of hPNPaseold-35 resulted in significant gene expression changes associated with mitochondrial dysfunction and cholesterol biosynthesis; whereas overexpression of hPNPaseold-35 caused global changes in cell-cycle related functions. Additionally, comparative gene expression analyses between our hPNPaseold-35 knockdown and overexpression datasets allowed us to identify 77 potential “direct” and 61 potential “indirect” targets of hPNPaseold-35 which formed correlated networks enriched for cell-cycle and wound healing functional association, respectively. These results provide a comprehensive database of genes responsive to hPNPaseold-35 expression levels; along with the identification new potential candidate genes offering fresh insight into cellular pathways regulated by PNPT1 and which may be used in the future for possible therapeutic intervention in mitochondrial- or inflammation-associated disease phenotypes.
Highlights
Ribonucleases (RNases) are one of the central players involved in the regulation of post-transcriptional control of gene expression in both prokaryotes and eukaryotes [1,2]
Polynucleotide phosphorylase (PNPase) is an evolutionarily conserved phosphorolytic 39R59 exoribonuclease that belongs to the PDX family of proteins [4] and it plays a major role in RNA metabolism in bacteria, plants and humans
Most of these studies concentrated on studying the role of hPNPaseold-35 in reference to its mitochondrial location with special emphasis on mtRNA processing, maintenance of mitochondrial homeostasis and more recently its role in mitochondrial RNA import [9,23,24,25,26,27]
Summary
Ribonucleases (RNases) are one of the central players involved in the regulation of post-transcriptional control of gene expression in both prokaryotes and eukaryotes [1,2]. They are divided into two main categories, endo- and exo-ribonucleases. Numerous exoribonucleases identified in bacteria, Archaea and Eukarya have been placed under six major superfamilies, RBN, RNR, DEDD, PDX, RRP4 and 5PX [4,5]. Polynucleotide phosphorylase (PNPase) is an evolutionarily conserved phosphorolytic 39R59 exoribonuclease that belongs to the PDX family of proteins [4] and it plays a major role in RNA metabolism in bacteria, plants and humans. The human homolog of this gene (hPNPaseold-35) was identified in an overlapping pathway screen (OPS) intended to identify upregulated transcripts in terminally differentiated human melanoma cells and senescent progeroid fibroblasts [7]
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