nanoRNAse controls nucleotides homestasis and cell proliferation

Nucleotides and nanoRNA homeostasis characterization and targeting.

Phosphodiesterases (PDEs) are relevant for biological processes such as RNA homeostasis (exoribonucleases) and second messengers-mediated signal transduction, including mono- and dinucleotides; targeting of selected PDEs in different pathological processes may offer therapeutic strategies.

The recently acknowledged role of nanoRNAs in cellular homeostasis changed the relevance of this metabolites and their degradation: nanoRNAs are responsible for priming transcription and their degradation represents crucial steps for cellular RNA homeostasis. Many dedicated nanoRNA hydrolases have been identified so far, including c-di-GMP dependent PDE bearing the HD-GYP domain.

Recent findings indicated that the accumulation of nanoRNA is harmful for the growth of both bacteria and eukaryotes (particularly in mitochondria). Accumulation of nanoRNA inhibited RNA metabolism by decreasing the concentration of mononucleotides, leading to enzyme inhibition and metabolic disorders. As an example, knock out mutants of c-di-GMP and nanoRNA PDEs in Mycoplasma bovis abolished the capability to grow under cell culture conditions in the absence of nucleotides supplementation. 

These results point toward nanoRNAses as promising targets for the development of new chemotherapeutics against multidrug-resistant pathogenic mycoplasma species or proliferating cells.

The aim of this research is to target specific nanoRNAses, found to be involved in sensing and degrading nanoRNAs, taking advantage of consolidated expertise in targeting nucleotide-dependent enzymes and in characterizing kinetically PDEs. A medium throughput colorimetric assay has been developed to test nucleotide-based inhibitors.

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