Ribonucleases

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Ribbon model of the RNase A of domestic cattle ( Bos taurus ).

Ribonucleases , or RNases for short ( also incorrectly written RNases ), are enzymes that catalyze the hydrolytic cleavage of phosphodiester bonds in ribonucleic acid (RNA) chains . This reaction is part of the processing and degradation of RNA. RNases are found in all living things and form an indispensable part of cellular metabolism . About 50 RNases are known in humans, some of which consist of several subunits ( protein complexes ); nine human RNases are currently associated with rare hereditary diseases .

RNases belong to the class of nucleases . They are classified according to the point of attack and the reaction product. If the cleavage occurs in the middle of the RNA chain, endoribonucleases are involved , while exoribonucleases attack the specific end of the RNA chain. This can result in 5'-phosphomonoesters or others. The IUBMB Enzyme Commission has reserved the enzyme categories 3.1.26.- and 3.1.27.- for endonucleases and 3.1.13.- and 3.1.14.- for exonucleases, while nucleases that can break down both RNA and DNA ( 3.1.15.- and 3.1.16.-) hardly any examples are known. This can be single-stranded or double-stranded RNA; this criterion is not suitable for differentiating the RNases.

function

The RNases form a diverse group of enzymes, all of which cut the chain molecule RNA by severing a phosphoric acid ester bond to the ribose. They initially differ in whether they attack single- or double-stranded RNA or RNA / DNA hybrids. The function can be unspecific or restricted to the location of certain nucleotides or nucleotide sequences. Recycling is an important but not the only purpose. For example, the lifespan of tRNA must be limited so that protein synthesis can be controlled by means of gene regulation . RNases also take part in the processing of the cell's own RNA (essentially tRNA and rRNA). Furthermore, RNases can destroy the genome of invading RNA viruses and thus participate in the innate immune response . Ribonucleases can be inhibited with diethyl bicarbonate.

pathology

Polymorphisms are known of nine human RNases that can lead to rare hereditary diseases .

Gene name RNase OMIM Hereditary disease
ANG Angiogenin 611895 Increased risk of amyotrophic lateral sclerosis type 9
DICER1 Dicer 606241 Early childhood tumor (pleuroplumonal blastoma ) and multi- nodular goiter
DIS3L2 DIS3-like exonuclease 2 614184 Perlman syndrome
ELAC2 Phosphodiesterase ELAC 2 605367 Increased risk of prostate cancer
POP1 RNase subunit POP1 602486 Severe osteochondrodysplasia
RNASEH2A RNase HII
(subunit A)
606034 Aicardi-Goutières syndrome type 4
RNASET2 RNase T2 612944 Cystic leukoencephalopathy without megalencephaly .
TSEN2 tRNA-splicing ribonuclease
(subunit Sen2)
608753 Pontocerebellar hypoplasia type 2B
TSEN34 tRNA splicing ribonuclease
(subunit Sen34)
608754 Pontocerebellar hypoplasia type 2C

Endoribonucleases

RNase A

RNase A cleaves single-stranded RNA. It recognizes the two pyrimidines U and C and cleaves the phosphodiester bond at the 5 'position of the ribose of the nucleotide following U or C in the RNA chain . RNase A is found in sweat , among other things, and is also a digestive enzyme . In doing so, it also breaks down RNA viruses that could infect the body . Thus, the secretion of RNase A with sweat is one of the body's defense mechanisms. This secretion leads to the fact that RNase A is a very often extracellularly occurring "environmental nuclease".

A striking property of a protein is its high heat stability: RNase A can withstand cooking (i.e. 100 ° C) without denaturing . It is a widely used laboratory reagent. Ribonuclease A was one of the first biomolecules whose structure was determined. In 1967 two teams succeeded in doing this independently of each other.

RNase B

RNase B has the same amino acid sequence as RNase A and only differs in that it has N- glycosylation , which presumably accelerates the protein folding of RNase B compared to RNase A by shielding a hydrophobic surface of the protein with the glycosylation.

RNase H

RNase H is a non-specific endoribonuclease that recognizes RNA-DNA heteroduplexes and removes the RNA component. The RNA is split hydrolytically via an enzyme-bound bivalent metal ion. She fulfills u. a. an important function in the replication of DNA by removing the attached RNA primer . There are two sub-types. The RNase H1 is monomeric and binds to 2'OH groups of four consecutive ribonucleotides . There are two isoforms of RNase H1 , a nucleus isoform whose function is unknown, and a mitochondrial isoform, which is necessary for mitochondrial DNA replication. The RNase H2 consists of the three proteins RNASEH2A, RNASEH2B and RNASEH2C, which form a trimeric complex, the catalytic center being located in the protein RNASEH2A.

During replication, RNase H2 removes RNA monomers mistakenly built into the DNA, which are then replaced by the correct DNA monomers. During replication, instead of the correct deoxyribonucleotides, the corresponding ribonucleotides are incorporated with a frequency of one in a few thousand. The repair is necessary because RNA is far more susceptible to spontaneous hydrolysis than DNA.

If there is insufficient enzyme activity, e.g. B. by mutations in one of the three protein genes, the remaining ribonucleotides lead to genome instability up to strand breakage and accumulation of DNA segments. These can interrupt the cell cycle by activating the p53 signal pathway and lead to apoptosis . The accumulated DNA segments can then provoke an inflammatory reaction via the innate immune system , which corresponds to the pathogenesis of Aicardi-Goutières syndrome , in which mutations in one of the three RNase H2 genes are indeed often found. If the RNASEH2B is missing in the knockout mouse , this leads to early embryonic lethality even during gastrulation .

RNase P

The RNase P is a ribozyme ; H. In contrast to the vast majority of enzymes, it is not a pure protein, but has an RNA subunit that ensures efficient substrate recognition. Their function is to provide a precursor sequence in the processing of tRNA secede. It consists of two sub-units.

Exoribonucleases

RNase R

The RNase R is a 3 '→ 5' exoribonuclease that is involved in the degradation of mRNA in bacteria.

RNase D

The RNase D is a 3 '→ 5' exoribonuclease that is involved in the processing of the tRNA.

See also degradosome , exosome , P-body .

Individual evidence

  1. Gene Ontology: Ribonuclease activity (definition)
  2. ^ Gene Ontology: Ribonuclease activity (children of)
  3. OrphaNet: Perlman Syndrome
  4. OrphaNet: CLWM
  5. Kartha G: Tertiary structure of ribonuclease . In: Nature . 214, No. 5085, 1967, p. 234. doi : 10.1038 / 214234a0 . PMID 6034236 .
  6. Donald Voet, Judith G. Voet: Biochemistry, 4th Edition. John Wiley & Sons, 2010, ISBN 978-1-118-13993-6 . P. 381.
  7. Martin AM Reijns, Björn Rabe, Rachel E. Rigby, Pleasantine Mill, Katy R. Astell, Laura A. Lettice, Shelagh Boyle, Andrea Leitch, Margaret Keighren, Fiona Kilanowski, Paul S. Devenney, David Sexton, Graeme Grimes, Ian J. Holt, Robert E. Hill, Martin S. Taylor, Kirstie A. Lawson, Julia R. Dorin: Enzymatic Removal of Ribonucleotides from DNA Is Essential for Mammalian Genome Integrity and Development . Cell 2012, Volume 149, Issue 5, May 10, 2012, pp. 1008-1022, cell.com
  8. Jennifer A. Doudna, Thomas R. Cech: The chemical repertoire of natural ribozymes . In: Nature . tape 418 , no. 6894 , July 11, 2002, p. 222–228 , doi : 10.1038 / 418222a ( nature.com [accessed November 19, 2017]).

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