Of
Chargaff's
four
rules
on
DNA
base
quantity,
his
second
parity
rule
(PR-2)
is
the
most
contentious.
Various
biometricians
(e.g.,
Sueoka,
Lobry)
regarded
PR-2
compliance
as
a
non-adaptive
feature
of
modern
genomes
that
could
be
modeled
through
interrelations
among
mutation
rates.
However,
with
stem-loop
potential
was
considered
adaptively
relevant
by
biochemists
familiar
analyses
nucleic
acid
structure
Crick)
and
meiotic
recombination
Kleckner).
Meanwhile,
other
had
shown
complementarity
extended
beyond
individual
bases
(1-mers)
to
oligonucleotides
(k-mers),
possibly
reflecting
"advantageous
structure"
(Nussinov).
An
"introns
early"
hypothesis
(Reanney,
Forsdyke)
suggested
primordial
world
recombination-mediated
error-correction
requiring
genome-wide
have
evolved
prior
localized
intrusions
protein-encoding
(exons).
Thus,
genome
equivalent
one
long
intron.
Indeed,
when
assessed
order-dependent
component
(correcting
for
local
influences
GC%),
genes,
especially
evolving
rapidly
under
positive
Darwinian
selection,
display
high
intronic
potential.
This
suggests
forced
migration
from
neighboring
exons
competing
may
first
arisen
non-adaptively.
Primary
prototypic
structures
were
later
strengthened
their
adaptive
contribution
recombination.
contentious
views
actually
in
harmony.
Trends in Cell Biology,
Год журнала:
2024,
Номер
unknown
Опубликована: Июль 1, 2024
Adenosine
deaminase
acting
on
RNA
1
(ADAR1)
converts
adenosine
to
inosine
in
double-stranded
(dsRNA)
molecules,
a
process
known
as
A-to-I
editing.
ADAR1
deficiency
humans
and
mice
results
profound
inflammatory
diseases
characterised
by
the
spontaneous
induction
of
innate
immunity.
In
cells
lacking
ADAR1,
unedited
RNAs
activate
sensors.
These
include
melanoma
differentiation-associated
gene
5
(MDA5)
that
induces
expression
cytokines,
particularly
type
I
interferons
(IFNs),
protein
kinase
R
(PKR),
oligoadenylate
synthase
(OAS),
Z-DNA/RNA
binding
(ZBP1).
Immunogenic
'defused'
may
transcripts
from
repetitive
elements
other
long
duplex
RNAs.
Here,
we
review
these
recent
fundamental
discoveries
discuss
implications
for
human
diseases.
Some
tumours
depend
escape
immune
surveillance,
opening
possibility
unleashing
anticancer
therapies
with
inhibitors.
Frontiers in Molecular Biosciences,
Год журнала:
2024,
Номер
11
Опубликована: Июль 10, 2024
The
success
of
messenger
(m)RNA-based
vaccines
against
SARS-CoV-2
during
the
COVID-19
pandemic
has
led
to
rapid
growth
and
innovation
in
field
mRNA-based
therapeutics.
However,
mRNA
production,
whether
small
amounts
for
research
or
large-scale
GMP-grade
biopharmaceutics,
is
still
based
on
In
Vitro
Transcription
(IVT)
reaction
developed
early
1980s.
IVT
exploits
phage
RNA
polymerase
catalyze
formation
an
engineered
that
depends
a
linearized
DNA
template,
nucleotide
building
blocks,
as
well
pH,
temperature,
time.
But
depending
conditions
subsequent
purification
steps,
diverse
byproducts
such
dsRNA,
abortive
RNAs
RNA:DNA
hybrids
might
form.
Unwanted
byproducts,
if
not
removed,
could
be
formulated
together
with
full-length
cause
immune
response
cells
by
activating
host
pattern
recognition
receptors.
this
review,
we
summarize
potential
types
their
known
biological
activity,
how
they
can
impact
efficacy
safety
addition,
briefly
overview
non-nucleotide-based
contaminants
RNases,
endotoxin
metal
ions
that,
when
present
reaction,
also
influence
activity
drugs.
We
further
discuss
current
approaches
aimed
at
adjusting
improving
achieve
optimal
performance
medical
applications.
Innate
immunity
must
be
tightly
regulated
to
enable
sensitive
pathogen
detection
while
averting
autoimmunity
triggered
by
pathogen-like
host
molecules.
A
hallmark
of
viral
infection,
double-stranded
RNAs
(dsRNAs)
are
also
abundantly
encoded
in
mammalian
genomes,
necessitating
surveillance
mechanisms
distinguish
“self”
from
“nonself.”
ADAR1,
an
RNA
editing
enzyme,
has
emerged
as
essential
safeguard
against
dsRNA-induced
autoimmunity.
By
converting
adenosines
inosines
(A-to-I)
long
dsRNAs,
ADAR1
covalently
marks
endogenous
thereby
blocking
the
activation
cytoplasmic
dsRNA
sensor
MDA5.
Moreover,
beyond
its
function,
binding
impedes
innate
immune
sensors
PKR
and
ZBP1.
Recent
landmark
studies
underscore
utility
silencing
for
cancer
immunotherapy,
exploiting
ADAR1-dependence
developed
certain
tumors
unleash
antitumor
response.
In
this
perspective,
we
summarize
genetic
mechanistic
evidence
ADAR1's
multipronged
role
suppressing
dsRNA-mediated
explore
evolving
roles
immuno-oncology
target.
CNS Neuroscience & Therapeutics,
Год журнала:
2025,
Номер
31(1)
Опубликована: Янв. 1, 2025
ABSTRACT
Background
Adenosine
deaminase
action
on
RNA
1
(ADAR1)
can
convert
the
adenosine
in
double‐stranded
(dsRNA)
molecules
into
inosine
a
process
known
as
A‐to‐I
editing.
ADAR1
regulates
gene
expression
output
by
interacting
with
and
other
proteins;
plays
important
roles
development,
including
growth;
is
linked
to
innate
immunity,
tumors,
central
nervous
system
(CNS)
diseases.
Results
In
recent
years,
role
of
tumors
has
been
widely
discussed,
but
its
CNS
diseases
not
reviewed.
It
worth
noting
that
studies
have
shown
great
potential
treatment
neurodegenerative
diseases,
mechanisms
are
still
unclear.
Therefore,
it
necessary
elaborate
Conclusions
Here,
we
focus
effects
such
Aicardi–AicardiGoutières
syndrome,
Alzheimer's
disease,
Parkinson's
glioblastoma,
epilepsy,
amyotrophic
lateral
sclerosis,
autism.
We
also
evaluate
impact
ADAR1‐based
strategies
these
particular
development
new
technologies
microRNAs,
nanotechnology,
editing,
stem
cell
therapy.
hope
provide
directions
insights
for
future
editing
technology
brain
science
Inosine
(I),
resulting
from
the
deamination
of
adenosine
(A),
is
a
prominent
modification
in
human
transcriptome.
The
enzymes
responsible
for
conversion
to
inosine
mRNAs
are
ADARs
(adenosine
deaminases
acting
on
RNA).
introduces
layer
complexity
mRNA
processing
and
function,
as
it
can
impact
various
aspects
RNA
biology,
including
stability,
splicing,
translation,
protein
binding.
relevance
this
process
emphasized
growing
number
disorders
associated
with
dysregulated
A-to-I
editing
pathways.
Here,
we
describe
structure
stability
duplex
consequences
at
different
locations
mRNAs.
Furthermore,
highlight
specific
open
questions
regarding
interplay
between
formation
innate
immune
response.
In
this
article,
I
recount
my
memories
of
key
experiments
that
led
to
entry
into
the
RNA
editing/modification
field.
highlight
initial
observations
made
by
pioneers
in
ADAR
field,
and
how
they
fit
our
current
understanding
family
enzymes.
discuss
early
mysteries
have
now
been
solved,
as
well
those
still
linger.
Finally,
important,
outstanding
questions
acknowledge
hope
for
future
Abstract
Adenosine-to-inosine
(A-to-I),
one
of
the
most
prevalent
RNA
modifications,
has
recently
garnered
significant
attention.
The
A-to-I
modification
actively
contributes
to
biological
and
pathological
processes
by
affecting
structure
function
various
molecules,
including
double-stranded
RNA,
transfer
microRNA,
viral
RNA.
Increasing
evidence
suggests
that
plays
a
crucial
role
in
development
human
disease,
particularly
cancer,
aberrant
levels
are
closely
associated
with
tumorigenesis
progression
through
regulation
expression
multiple
oncogenes
tumor
suppressor
genes.
Currently,
underlying
molecular
mechanisms
cancer
not
comprehensively
understood.
Here,
we
review
latest
advances
regarding
editing
pathways
implicated
describing
their
functions
connections
disease.
Briefings in Bioinformatics,
Год журнала:
2025,
Номер
26(2)
Опубликована: Март 1, 2025
Abstract
A-to-I
ribonucleic
acid
(RNA)
editing
detection
is
still
a
challenging
task.
Current
bioinformatics
tools
rely
on
empirical
filters
and
whole
genome
sequencing
or
exome
data
to
remove
background
noise,
errors,
artifacts.
Sometimes
they
make
use
of
cumbersome
time-consuming
computational
procedures.
Here,
we
present
REDInet,
temporal
convolutional
network-based
deep
learning
algorithm,
profile
RNA
in
human
(RNAseq)
data.
It
has
been
trained
REDIportal
sites,
the
largest
collection
changes
from
>8000
RNAseq
genotype-tissue
expression
project.
REDInet
can
classify
events
with
high
accuracy
harnessing
nucleotide
frequencies
101-base
windows
without
need
for
coupled
genomic
