RNase P: Beyond Precursor tRNA Processing

Abstract

Ribonuclease P (RNase P) was first described in the 1970’s as an endoribonuclease acting in the maturation of precursor transfer RNAs (tRNAs). More recent studies, however, have uncovered non-canonical roles for RNase P and its components. Here, we review the recent progress of its involvement in chromatin assembly, DNA damage response, and maintenance of genome stability with implications in tumorigenesis. The possibility of RNase P as a therapeutic target in cancer is also discussed.

1. Introduction

As a ribozyme, ribonuclease P (RNase P) was initially discovered in Escherichia coli [1,2], which is participated in the maturation of transfer RNAs (tRNAs), 4.5S RNA, riboswitches, and messenger RNAs (mRNAs) [3–7]. This ribozyme processes the 50 leader sequences of precursor tRNAs (pre-tRNAs) and leaves a mature 50 terminus and 30 hydroxyl group on the leader sequence by hydrolyzing the phosphodiester bond within the RNA backbone [8,9]. As its activity relies on Mg2+ ions, RNase P is classed as a metalloenzyme [10]. In human, RNase P from nucleus is composed of up to ten protein subunits and a catalytic RNA component, H1 [11]. Remarkably, RNase P has several common protein subunits with two other eukaryotic ribonucleoprotein enzymes, i.e., ribonuclease mitochondrial RNA processing (RNase MRP) and telomerase, which have distinct catalytic RNA components [12,13]. RNase MRP processes precursor ribosomal RNAs (rRNAs) by cleavage at specific sites [14,15], while telomerase protects telomeres from shortening during successive cell divisions by the addition of repetitive sequences to chromosome ends [16,17]. The sharing of subunits suggests that the protein subunits may be able to separate from the holoenzymes and participate in other intracellular processes.

Recent research progress reveals that RNase P and its components interact with various RNA substrates and get involved in transcription regulation or genome homeostasis maintenance, thus, have several non-canonical functions. First of all, purified RNase P from HeLa cells is proved to promote the maturation of mRNAs transcribed from RNA polymerase II (RNA Pol II) [4]. Protein components of RNase P are also reported to bind to RNA polymerase I (RNA Pol I) subunits and rRNA gene loci, interfering with the processing of rRNAs, although the precise mechanism remains unclear [18–21]. Moreover, RNase P RNA component regulates the transcription of 5S rRNAs transcribed from RNA polymerase III (RNA Pol III) [22]. Several protein components of RNase P bind to H3.3 (a histone H3 variant that regulates chromatin organization), compromising chromatin assembly and genome stabilization [23,24]. The genome suffers from continual assaults, both external and intrinsic, which can result in vast number of DNA damages, including DNA double-strand breaks (DSBs), which results in completely breakages of two DNA strands. Such damage triggers cells to mobilize and coordinate cellular activities to repair the damaged DNA in order to maintain genomic stability and integrity [25,26]. Intriguingly, two unique subunits of RNase P, RPP21 and RPP29, are found to be recruited at DSB sites, promoting homologous recombination (HR)-mediated DNA repair [27]. Furthermore, subunits of yeast RNase P are also involved in stabilizing the RNA component of telomerase, thereby protecting the ends of chromosomes [28].

Here, we summarize recent findings about RNase P assembly as well as non-canonical functions of RNase P and its components which are involved in a variety of cellular processes including chromatin assembly, DNA damage response, genome stability maintenance, and tumorigenesis. Furthermore, we discuss its potential in therapeutic drug development.