Human RNase P: overview of a ribonuclease of interrelated molecular networks and gene-targeting systems

Abstract

The seminal discovery of ribonuclease P (RNase P) and its catalytic RNA by Sidney Altman has not only revolutionized our understanding of life, but also opened new fields for scientific exploration and investigation. This review focuses on human RNase P and its use as a gene targeting tool, two topics initiated in Altman’s laboratory. We outline early works on human RNase P as a tRNA processing enzyme and comment on its expanding non-conventional functions in molecular networks of transcription, chromatin remodelling, homology-directed repair and innate immunity. The important implications and insights from these discoveries on the potential use of RNase P as a gene targeting tool are presented. This multifunctionality calls to a modified structure-function partitioning of domains in human RNase P, as well as its relative ribonucleoprotein, RNase MRP. The role of these two catalysts in innate immunity is of particular interest in molecular evolution, as this dynamic molecular network could have originated and evolved from primordial enzymes and sensors of RNA, including predecessors of these two ribonucleoproteins.

Novel phenotype associated with homozygous likely pathogenic variant in the POP1 gene

“…RNAse P is found both in the cytoplasm and mitochondria and functions in maturation of tRNA molecules. 6,7 Both ribonucleoproteins are evolutionary and structurally related. POP1, is one of 11 interacting proteins of these complexes, composed of a short N-terminal domain, internal motif and a large C-terminal motif.…”

“…Alternative splicing in the POP1 gene results in multiple transcript variants with no tissue specifity. [6][7][8] Previous studies have shown that mutations in POP1, lead to RMRP depletion, suggesting that alterations in ribosomal biogenesis are a major pathogenic mechanism for severe short stature and skeletal dysplasia. 9,10 Our patient's RMRP level is lower than in reported cases, the same holds for the increase in Pre-5.8S.…”

“…Another variant at the same position c.449G > A; p.Arg150His (NM_001145860.2) is submitted as a VUS in ClinVar. This domain is common to both RNase MRP and RNase P ribonucloproteins and plays a crucial role in pre-tRNA substrate recognition, [6][7][8][9][10][11][12] which is essential for the precise translation process. Disturbances in tRNA recognition may result in irreversible consequences and have been proposed to contribute to various anomalies and neurodevelopmental disorders.…”

“…The POP1 gene encodes the protein, known as processing of precursor RNA1 (POP1), shared by two highly essential ribonucleoprotein complexes, RNAse MRP and RNAse P. RNAse MRP (RMRP) is a highly conserved ribonucleoprotein complex, responsible for processing pre‐RNA in the mitochondria. RNAse P is found both in the cytoplasm and mitochondria and functions in maturation of tRNA molecules 6,7 . Both ribonucleoproteins are evolutionary and structurally related.…”

A RNase P Ribozyme Inhibits Gene Expression and Replication of Hepatitis B Virus in Cultured Cells

“…Because of this, the M1GS ribozyme can be used to target both cytoplasmic and nuclear mRNAs while the EGS-mediated gene targeting action to downregulate gene expression is believed to work in the nuclei where human RNase P is primarily localized [ 38 ]. Moreover, the M1GS ribozyme is different from human RNase P, which contains at least 10 different protein subunits and a RNA subunit (H1 RNA), which is hardly catalytically active in the absence of the protein subunits [ 3 , 40 ].…”