Transcript Glimpses of a few literatures on snRNA

Glimpses of a little
literature on
small RNA
Ali Ghanbari
March 2006
Ghanbari
The antiquity of RNA-based evolution
Gerald F. Joyce
Departments of Chemistry and Molecular Biology and The Skaggs Institute for Chemical
Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037, USA (e-mail: [email protected])
NATURE | VOL 418 | 11 JULY 2002 |
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The dawn of darwinian evolution
A cluttered path to RNA
RNA-catalysed RNA replication
Metabolic function in the RNA world
Transition to the DNA–protein world
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1960‘s ncRNA RNA, that catalyse
nucleotide synthesis RNA
polymerization,aminoacylation of transfer
RNA and peptide bond formation
1982 Ribozyme
RNAse
ribonuclerase
The discovery of RNA interference
petunias 1990
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(PTGS)
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Some titles concerning about the
small RNA
fRNA
sRNA
smRNA
ncRNA
siRNA
snRNA (small nucleus)
scRNA
snoRNA( small nucleolar RNAs)
RNAi
stRNA
snmRNA
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Recent efforts of several laboratories have brought
together two fascinating forms of gene regulation:
silencing genes by degrading their mRNAs,and
blocking translation of specific mRNAs during
development.Both of these processes involve very
small RNAs,about 22nt in length.
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RNA interference
Gregory J. Hannon
Cold Spring Harbour Laboratory, 1 Bungtown Road, Cold Spring Harbour, New York
11724, USA (e-mail: [email protected])
NATURE | VOL 418 | 11 JULY 2002
RNA interference: It’s a small RNA world
Eric G. Moss
Current Biology 2001, 11:R772–R775
Short RNAs regulate gene expression in many species.
Some are generated from any double-stranded RNA and
degrade complementary RNAs; others are encoded by
genes and repress specific mRNAs. Both, it turns out, are
processed and handled by similar proteins. These
pathways offer a glimpse into a world of small RNAs.
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To identify more small regulatory RNAs of the lin4/let-7 class in C. elegans, we used informatics and
cDNA cloning to select C. elegans genomic
sequences that exhibited four characteristics of lin4 and let-7: (i) expression of a mature RNA of ;22 nt
in of a mature RNA of ;22 nt incoding) sequences;
(iii) high DNA se-quence similarity between
orthologs in C. elegans and a related species,
Caenorhabditis briggsae; and (iv) processing of
the ;22-ntmature RNA from a stem-loop precursor
transcript of ;65 nt (2, 3).
An Extensive Class of Small RNAs in
Caenorhabditis elegans
Rosalind C. Lee and Victor
Ghanbari Ambros*
March 2006
The first of these was that let-7 RNA is
phylogenetically conserved—in size and nucleotide
sequence- in essentially all the bilaterally symmetric
animals (Pasquinelli et al., 2000 Nature).
A second discovery that supported the relative
ubiq-uity of tiny RNAs like lin-4 (1993)and let7(2000) was the finding that small antisense
RNAs of about 22 nt in length (called siRNAs)
are central to RNA interference (RNAi) (see
Sharp, 2001 Gene Dev. and references therein).
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alternative splicing
For example, exons can be extended or shortened,
skipped or included, and introns can be removed or
retained in the mRNA
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A general mechanisms of alternative splicing
RNA Silencing: The Genome’s
Immune System
Ronald H. A. Plasterk
Scienc vol 296 2002
Genomes are databases sensitive to invasion by viruses. In recent
years, a
defense mechanism has been discovered, which turns out to be
conserved
among eukaryotes. The system can be compared to the immune
system in
several ways: It has speciÞcity against foreign elements and the
ability to
March 2006and raise a massive response
Ghanbari against an invading nucleic
amplify
acid. The
Over the years, a number of RNAs that do not function as
messenger RNAs (mRNAs), transfer RNAs (tRNAs), or ribosomal
RNAs (rRNAs) have been discovered,mostly fortuitously. The
non-mRNAs have been given a variety of names (1, 2); the term
small RNAs (sRNAs) has been pre-dominant in bacteria,
whereas the term noncoding RNAs (ncRNAs) has been predominant in eukaryotes and will be used here. ncRNAs range in
size from 21 to 25 nt for the large family of microRNAs (miRNAs)
that modulate development in Caenorhabditis elegans,
Drosophila, and mammals (3–8), up to ;100 to 200 nt for sRNAs
commonly found as translational regulators in bacterial cells (9,
10) and to 10,000 nt for RNAs involved in gene silencing in
higher eukaryotes (11–13). The functions described for ncRNAs
thus far `are extremely varied (Table 1).
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Table 1 Naturally occurring ribozymes and ribonucleoprotein enzymes
Ribozyme
Sequenced Size
Activity (reaction product)
examples (nt)
Hammerhead 11 40 Self-cleavage via
Hepatitis delta virus 2 90 transesterification (28,38 cyclic
Hairpin 1 70 phosphate)
Varkud satellite 1 160
Group I intron >1,500 210 Self-splicing via
Group II intron >700 500 transesterification (38-OH)
RNase P* >500 300 Pre-tRNA processing via
hydrolysis (38-OH)
Spliceosome* 70,50 180,100 RNA splicing via
(U2+U6 snRNAs) transesterification (38-OH)
Ribosome* >900 2,600 Peptidyl transfer (amide)
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(23S2006
rRNA)
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Number of sequenced examples is a snapshot as of 2002 and
is influenced by DNA-sequencing strategies and database
upkeep; it may provide a rough indication of relative
abundance. RNAs in any group vary in size; the size
provided here indicates the lower end of the length
distribution for the natural examples.
Ribonucleoprotein enzymes. RNase P: bacterial and
archaebacterial RNAs have the relevant activity in the
absence of protein. Spliceosome: U2 and U6 small nuclear
RNAs (snRNAs) alone show an activity related to the
natural activity. Ribosome: no activity has yet been observed
with protein-free, large-subunit rRNA.
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The spreading signal may be the siRNAs
itself, which could be continuously
produced in cells that express dsRNA. It
could also be envisioned that the siRNAs
are replicated by the action of RdRPs.
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Processes affected by ncRNAs.
Process
Example
Function
Transcription
184-nt E. coli 6S
Modulates promoter use
331-nt human 7SK
Inhibits transcription
factor P-TEFb
Steroid receptor
elongation
875-nt human SRA
coactivator
Gene silencing
chromosome I
nactivation
16,500-nt human Xist
Required for X-
100,000-nt human Air
Required for autosomal
gene imprinting Replication
451-nt human telomerase RNA
Core of telomerase
and
telomere template
RNA processing
377-nt E. coli RNase P Catalytic core of RNase
186-nt human U2 snRNA Core of spliceosome
RNA modification
of
Directs 2’-O-ribose methylation
target rRNA
189-nt S. cerevisiae snR8 H/ACA snoRNA Directs pseudouridylation of
target rRNA
102-nt S. cerevisiae U18 C/D snoRNA
68-nt T. brucei gCYb gRNA
excision of
RNA stability
80-nt E. coli RyhB sRNA
Eukaryotic miRNA?
mRNA translation
109-nt E. coli OxyS
occluding
binding
Directs the insertion and
uridines
Targets mRNAs for degradation?
Targets mRNAs for degradation?
Represses translation by
ribosome
87-nt E. coli DsrA sRNA
preventing
inhibitory mRNA structure
translation by pairing with
end of target mRNA
Protein stability
on
Protein Translocation
recognition
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membranes
Activates translation by
formation of an
22-nt C. elegans lin-4 miRNA
Represses
39
363-nt E. coli tmRNA
Directs addition of tag to peptides
stalled ribosomes
114-nt E. coli 4.5S RNA
Integral component of signal
particle central to protein translocation across
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Table 1 Naturally occurring ribozymes and
ribonucleoprotein enzymes
Ribozyme Sequenced Size Activity (reaction product)
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Higher eukaryotes can mount antiviral immune
responses induced by dsRNA. This process, called
RNA interference, is sequence specific and can
therefore be used to target gene expression.
Nature Immunology 3, 597 - 599 (2002)
doi:10.1038/ni0702-597
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1 According to one model for RNA
silencing, there are two stages during which
RNA is cleaved. a, In the first stage in
Drosophila, the enzyme Dicer (identified by
Bernstein et al.1) binds to double-stranded
RNA produced by a virus or by mobile
DNA, or introduced experimentally. Dicer
cleaves the double-stranded RNA into
fragments of 22 nucleotides each. b, Dicer
then associates through its so-called PAZ
domain with a relative of ARGONAUTE,
another PAZ-domain-containing protein.c,
This association would allow the 22nucleotide RNA to be transferred to an
RNase associated with the ARGONAUTE
relative, guiding the RNase to singlestranded messenger RNAs that match the
22-nucleotide RNA. The RNase would then
cleave the single-stranded RNAs (not
shown).
Emerging clinical applications of RNA
RNA as a protein antagonist
Immunotherapy using mRNAtransfected dendritic cells
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The small RNAs we know of
may only be the tip of an iceberg.
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Our intention:
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