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Auto-hydrolysis
The hydrolysis or cleavage of RNA can occur spontaneously, without the presence of a catalyst
or enzyme. This process is known as an auto-hydrolysis or a self-cleavage reaction.
Spontaneous cleavage in an RNA molecule is much more likely to occur when it is single-
stranded.[2] Auto-hydrolysis or self-cleavage reactions take place in basic solutions, where free
hydroxide ions in solution can easily deprotonate the 2’ OH of the ribose. This deprotonation
makes the reaction base-catalyzed and increases spontaneity of the reaction.[2]
Enzyme cleavage
When the RNA is double-stranded or involved in nucleotide base pairing, it is more stable and
spontaneous cleavage is significantly less likely. In these instances, cleavage is done using
catalytic enzymes. Several different enzymes catalyze cleavage at specific sites on an RNA
molecule.[2]
One such enzyme is Ribonuclease A (RNase A), a protein enzyme. RNase A contains histidine in
its active site, and uses it to accomplish acid-base catalysis and cleavage of RNA.[2] Certain
histidine residues in the active site act as bases to remove protons from 2’ hydroxyls of ribose
sugars, while others act as acids to donate protons to the 5’ oxygen of adjacent riboses to make
them better leaving groups. A lysine residue, also in the active site of RNase A, stabilizes the
negatively charged oxygen atoms in the transition state.[2]
A category of ribozymes called small ribonucleolytic ribozymes enhances the spontaneity of the
cleavage of their own RNA using acid-base catalysis. Examples of such ribozymes include the
hammerhead ribozyme, the Hepatitis Delta Virus (HDV) ribozyme, and the hairpin ribozyme.[2]
Large ribozymes, such as Group I introns, Group II introns, and RNase P, catalyze splicing and
other post-trascriptional modifications during mRNA processing, using the cleavage mechanism
described above.[2]
Possible applications
Researchers are developing and using various applications for RNA hydrolysis that can be
carried out in a controlled way. Applications include the use of ribozymes in gene therapy to
control gene expression in bacteria and eukaryotes, and to inhibit viral replication.[2]
Hammerhead ribozymes, in particular, can be designed such that they will cleave a desired
RNA.[3] These ribozymes can be designed to prevent expression of a particular gene, for
example.[4]
In addition to inhibiting gene expression, splicing ribozymes can be used to repair damaged or
defective RNA. Splicing ribozymes catalyze RNA splicing, removing a section of RNA that
contains a mutation and replacing it with well-functioning RNA.[5] Existing ribozymes can also be
altered in a way that changes the reaction(s) that the ribozyme catalyzes.[6]
References
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