Ribonuclease P (, ''RNase P'') is a type of
ribonuclease
Ribonuclease (commonly abbreviated RNase) is a type of nuclease that catalyzes the degradation of RNA into smaller components. Ribonucleases can be divided into endoribonucleases and exoribonucleases, and comprise several sub-classes within ...
which cleaves
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
. RNase P is unique from other RNases in that it is a
ribozyme
Ribozymes (ribonucleic acid enzymes) are RNA molecules that have the ability to catalyze specific biochemical reactions, including RNA splicing in gene expression, similar to the action of protein enzymes. The 1982 discovery of ribozymes demonst ...
– a ribonucleic acid that acts as a catalyst in the same way that a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
-based enzyme would. Its function is to cleave off an extra, or precursor, sequence of RNA on
tRNA
Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes), that serves as the physical link between the mRNA and the amino ac ...
molecules.
Further, RNase P is one of two known multiple turnover ribozymes in nature (the other being the
ribosome
Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to ...
), the discovery of which earned
Sidney Altman
Sidney Altman (May 7, 1939 – April 5, 2022) was a Canadian-American molecular biologist, who was the Sterling Professor of Molecular, Cellular, and Developmental Biology and Chemistry at Yale University. In 1989, he shared the Nobel Prize in ...
and
Thomas Cech
Thomas Robert Cech (born December 8, 1947) is an American chemist who shared the 1989 Nobel Prize in Chemistry with Sidney Altman, for their discovery of the catalytic properties of RNA. Cech discovered that RNA could itself cut strands of RNA, ...
the
Nobel Prize in Chemistry
)
, image = Nobel Prize.png
, alt = A golden medallion with an embossed image of a bearded man facing left in profile. To the left of the man is the text "ALFR•" then "NOBEL", and on the right, the text (smaller) "NAT•" then "M ...
in 1989: in the 1970s, Altman discovered the existence of precursor tRNA with flanking sequences and was the first to characterize RNase P and its activity in processing of the
5' leader sequence of precursor tRNA. Recent findings also reveal that RNase P has a new function.
It has been shown that human nuclear RNase P is required for the normal and efficient transcription of various
small noncoding RNAs, such as tRNA,
5S rRNA,
SRP RNA and
U6 snRNA
U6 snRNA is the non-coding small nuclear RNA (snRNA) component of U6 snRNP (''small nuclear ribonucleoprotein''), an RNA-protein complex that combines with other snRNPs, unmodified pre-mRNA, and various other proteins to assemble a spliceosome, ...
genes,
which are transcribed by
RNA polymerase III
In eukaryote cells, RNA polymerase III (also called Pol III) is a protein that transcribes DNA to synthesize ribosomal 5S rRNA, tRNA and other small RNAs.
The genes transcribed by RNA Pol III fall in the category of "housekeeping" genes whose e ...
, one of three major nuclear RNA polymerases in human cells.
In Bacteria
Bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
l RNase P has two components: an RNA chain, called M1 RNA, and a polypeptide chain, or protein, called C5 protein.
''
In vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
'', both components are necessary for the ribozyme to function properly, but ''
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
'', the M1 RNA can act alone as a catalyst.
The primary role of the C5 protein is to enhance the substrate binding affinity and the catalytic rate of the M1 RNA enzyme probably by increasing the metal ion affinity in the active site. The crystal structure of a bacterial RNase P holoenzyme with tRNA has been recently resolved, showing how the large, coaxially stacked helical domains of the RNase P RNA engage in shape selective recognition of the pre-tRNA target. This crystal structure confirms earlier models of substrate recognition and catalysis, identifies the location of the active site, and shows how the protein component increases RNase P functionality.
Bacterial RNase P class A and B
Ribonuclease P (RNase P) is a ubiquitous endoribonuclease, found in archaea, bacteria and eukarya as well as chloroplasts and mitochondria. Its best characterised activity is the generation of mature 5'-ends of tRNAs by cleaving the 5'-leader elements of precursor-tRNAs. Cellular RNase Ps are
ribonucleoprotein
Nucleoproteins are proteins conjugated with nucleic acids (either DNA or RNA). Typical nucleoproteins include ribosomes, nucleosomes and viral nucleocapsid proteins.
Structures
Nucleoproteins tend to be positively charged, facilitating in ...
s (RNP). RNA from bacterial RNase Ps retains its catalytic activity in the absence of the protein subunit, i.e. it is a ribozyme. Isolated eukaryotic and archaeal RNase P RNA has not been shown to retain its catalytic function, but is still essential for the catalytic activity of the holoenzyme. Although the archaeal and eukaryotic holoenzymes have a much greater protein content than the eubacterial ones, the RNA cores from all the three lineages are homologous—helices corresponding to P1, P2, P3, P4, and P10/11 are common to all cellular RNase P RNAs. Yet, there is considerable sequence variation, particularly among the eukaryotic RNAs.
In Archaea
In
archaea
Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaebac ...
, RNase P
ribonucleoprotein
Nucleoproteins are proteins conjugated with nucleic acids (either DNA or RNA). Typical nucleoproteins include ribosomes, nucleosomes and viral nucleocapsid proteins.
Structures
Nucleoproteins tend to be positively charged, facilitating in ...
s consist of 4–5 protein subunits that are associated with RNA. As revealed by ''in vitro'' reconstitution experiments these protein subunits are individually dispensable for tRNA processing that is essentially mediated by the RNA component.
The structures of protein subunits of archaeal RNase P have been resolved by
x-ray
An X-ray, or, much less commonly, X-radiation, is a penetrating form of high-energy electromagnetic radiation. Most X-rays have a wavelength ranging from 10 picometers to 10 nanometers, corresponding to frequencies in the range 30&nb ...
crystallography
Crystallography is the experimental science of determining the arrangement of atoms in crystalline solids. Crystallography is a fundamental subject in the fields of materials science and solid-state physics (condensed matter physics). The wor ...
and
NMR
Nuclear magnetic resonance (NMR) is a physical phenomenon in which nuclei in a strong constant magnetic field are perturbed by a weak oscillating magnetic field (in the near field) and respond by producing an electromagnetic signal with ...
, thus revealing new protein domains and folding fundamental for function.
Using
comparative genomics and improved computational methods, a radically minimized form of the RNase P RNA, dubbed "Type T", has been found in all complete genomes in the crenarchaeal phylogenetic family Thermoproteaceae, including species in the genera Pyrobaculum, Caldivirga and Vulcanisaeta.
All retain a conventional catalytic domain, but lack a recognizable specificity domain. 5′ tRNA processing activity of the RNA alone was experimentally confirmed. The Pyrobaculum and Caldivirga RNase P RNAs are the smallest naturally occurring form yet discovered to function as trans-acting ribozymes.
Loss of the specificity domain in these RNAs suggests potential altered substrate specificity.
It has recently been argued that the archaebacteriium ''Nanoarchaeum equitans'' does not possess RNase P. Computational and experimental studies failed to find evidence for its existence. In this organism the tRNA promoter is close to the tRNA gene and it is thought that transcription starts at the first base of the tRNA thus removing the requirement for RNase P.
In eukaryotes
In
eukaryotes
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
, such as humans and
yeast
Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constitut ...
,
[Randall Munroe rephrased this as “You know, eukaryotes—like sourdough starter or Conan O’Brien.” ()] most RNase P consists of an RNA chain that is structurally similar to that found in bacteria
as well as nine to ten associated proteins (as opposed to the single bacterial RNase P protein, C5).
Five of these protein subunits exhibit homology to archaeal counterparts. These protein subunits of RNase P are shared with
RNase MRP
RNase MRP (also called RMRP) is an enzymatically active ribonucleoprotein with two distinct roles in eukaryotes. RNAse MRP stands for RNAse for mitochondrial RNA processing. In mitochondria it plays a direct role in the initiation of mitochondria ...
,
a catalytic ribonucleoprotein involved in processing of ribosomal RNA in the
nucleolus
The nucleolus (, plural: nucleoli ) is the largest structure in the nucleus of eukaryotic cells. It is best known as the site of ribosome biogenesis, which is the synthesis of ribosomes. The nucleolus also participates in the formation of sig ...
.
RNase P from eukaryotes was only recently demonstrated to be a ribozyme.
Accordingly, the numerous protein subunits of eucaryal RNase P have a minor contribution to tRNA processing per se,
while they seem to be essential for the function of RNase P and RNase MRP in other biological settings, such as gene transcription and the
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
.
Despite the bacterial origins of mitochondria and chloroplasts, plastids from higher animals and plants do not appear to contain an RNA-based RNase P. It has been shown that human mitochondrial RNase P is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
and does not contain
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
.
Spinach
Spinach (''Spinacia oleracea'') is a leafy green flowering plant native to central and western Asia. It is of the order Caryophyllales, family Amaranthaceae, subfamily Chenopodioideae. Its leaves are a common edible vegetable consumed either f ...
chloroplast
A chloroplast () is a type of membrane-bound organelle known as a plastid that conducts photosynthesis mostly in plant and algal cells. The photosynthetic pigment chlorophyll captures the energy from sunlight, converts it, and stores it in ...
RNase P has also been shown to function without an RNA subunit.
Therapies using RNase P
RNase P is now being studied as a potential therapy for diseases such as
herpes simplex virus
Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known by their taxonomical names ''Human alphaherpesvirus 1'' and '' Human alphaherpesvirus 2'', are two members of the human ''Herpesviridae'' family, a set of viruses that produce viral inf ...
,
cytomegalovirus
''Cytomegalovirus'' (''CMV'') (from ''cyto-'' 'cell' via Greek - 'container' + 'big, megalo-' + -''virus'' via Latin 'poison') is a genus of viruses in the order ''Herpesvirales'', in the family ''Herpesviridae'', in the subfamily ''Betaherpe ...
,
influenza
Influenza, commonly known as "the flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms ...
and other respiratory infections,
HIV-1
and cancer caused by fusion gene
BCR-ABL
The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defective and unusually short becaus ...
.
External guide sequences (EGSs) are formed with
complementarity to viral or oncogenic mRNA and structures that mimic the T loop and acceptor stem of
tRNA
Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes), that serves as the physical link between the mRNA and the amino ac ...
.
These structures allow RNase P to recognize the EGS and cleave the target mRNA. EGS therapies have shown to be effective in culture and in live mice.
References
Further reading
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External links
Nobel Lecture of Sidney Altman Nobel prize in Chemistry 1989
at ncsu.edu
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Ribonucleases
Ribozymes
RNA splicing
EC 3.1.26
Ribonucleoproteins