Nature,
Journal Year:
2024,
Volume and Issue:
635(8037), P. 237 - 242
Published: Oct. 9, 2024
Abstract
The
interplay
between
translation
and
mRNA
decay
is
widespread
in
human
cells
1–3
.
In
quality-control
pathways,
exonucleolytic
degradation
of
associated
with
translating
ribosomes
mediated
largely
by
the
cytoplasmic
exosome
4–9
,
which
includes
exoribonuclease
complex
EXO10
helicase
SKI238
(refs.
10–16
).
can
extract
from
ribosome
expected
to
transfer
it
core
through
a
bridging
factor,
HBS1L3
(also
known
as
SKI7),
but
mechanisms
this
molecular
handover
remain
unclear
7,17,18
Here
we
reveal
how
recruited
(SKI7)
an
active
ribosome-bound
complex.
We
show
that
rather
than
sequential
handover,
direct
physical
coupling
mechanism
takes
place,
culminates
formation
exosome–ribosome
supercomplex.
Capturing
structure
during
reveals
continuous
path
RNA
substrate
threads
80S
SKI2
into
site
SKI3
subunit
directly
binds
also
engages
surface
40S
subunit,
establishing
recognition
platform
collided
disomes.
Exosome
thus
work
together
single
structural
functional
unit
co-translational
decay,
coordinating
their
activities
transient
The EMBO Journal,
Journal Year:
2023,
Volume and Issue:
42(19)
Published: Aug. 22, 2023
Abstract
mRNA
surveillance
pathways
are
essential
for
accurate
gene
expression
and
to
maintain
translation
homeostasis,
ensuring
the
production
of
fully
functional
proteins.
Future
insights
into
quality
control
will
enable
us
understand
how
cellular
levels
controlled,
defective
or
unwanted
mRNAs
can
be
eliminated,
dysregulation
these
contribute
human
disease.
Here
we
review
translation‐coupled
mechanisms,
including
non‐stop
no‐go
decay
pathways,
describing
their
shared
trans‐acting
factors,
differences.
We
also
describe
advances
in
our
understanding
nonsense‐mediated
(NMD)
pathway,
highlighting
recent
mechanistic
findings,
discovery
novel
as
well
role
NMD
physiology
its
impact
on
Nature,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Feb. 12, 2025
Abstract
Duchenne
muscular
dystrophy
(DMD)
is
a
muscle-degenerating
disease
caused
by
mutations
in
the
DMD
gene,
which
encodes
dystrophin
protein
1,2
.
Utrophin
(
UTRN
),
genetic
and
functional
paralogue
of
,
upregulated
some
patients
3–5
To
further
investigate
this
upregulation,
we
first
developed
an
inducible
messenger
RNA
(mRNA)
degradation
system
for
introducing
premature
termination
codon
(PTC)
one
its
alternatively
spliced
exons.
Inclusion
PTC-containing
exon
triggers
mutant
mRNA
decay
upregulation.
Notably,
blocking
nonsense-mediated
results
reversal
whereas
overexpressing
does
not.
Furthermore,
PTC
minigenes
wild-type
cells
causes
as
minigene
containing
self-cleaving
ribozyme.
place
these
findings
therapeutic
context,
used
splice-switching
antisense
oligonucleotides
(ASOs)
to
induce
skipping
out-of-frame
exons
aiming
introduce
PTCs.
We
found
that
ASOs
cause
In
addition,
when
using
ASO
restore
reading
frame
myotubes
derived
from
patient,
actual
treatment,
upregulation
was
reduced.
Altogether,
indicate
decay-based
mechanism
called
transcriptional
adaptation
6–8
plays
key
role
patients,
they
highlight
unexplored
application
ASOs,
well
ribozymes,
inducing
compensation
via
adaptation.
Cell,
Journal Year:
2025,
Volume and Issue:
188(4), P. 885 - 900
Published: Feb. 1, 2025
RNA
plays
a
central
role
in
protein
biosynthesis
and
performs
diverse
regulatory
catalytic
functions,
making
it
essential
for
all
processes
of
life.
Like
DNA,
is
constantly
subjected
to
damage
from
endogenous
environmental
sources.
However,
while
the
DNA
response
has
been
extensively
studied,
was
long
assumed
that
lesions
are
relatively
inconsequential
due
transient
nature
most
molecules.
Here,
we
review
recent
studies
challenge
this
view
by
revealing
complex
responses
determine
survival
when
cells
exposed
nucleic
acid-damaging
agents
promote
resolution
lesions.
Trends in Genetics,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Jan. 1, 2025
HighlightsMany
dominant
diseases
are
still
poorly
understood
from
a
genetic
and
molecular
perspective.Transcriptional
adaptation
(TA)
is
newly
identified
cellular
response
involving
mRNA
decay.TA
can
lead
to
changes
in
gene
expression
resulting
compensation
or
worsening
of
the
phenotype.We
posit
that
some
thought
be
caused
by
haploinsufficiency
actually
due
gain-of-function
effects
via
TA.AbstractThe
onset
progression
result
negative
effects.
Here,
we
propose
transcriptional
(TA),
decay,
as
an
additional
cause
diseases.
TA
modulates
so-called
adapting
genes,
likely
decay
products,
phenotype.
Recent
studies
have
challenged
current
concepts
poison
proteins
mechanisms
underlying
certain
diseases,
including
Brugada
syndrome,
hypertrophic
cardiomyopathy,
frontotemporal
lobar
degeneration.
We
hypothesize
for
these
other
when
mutation
leads
phenotype
at
least
partly
dysregulation
TA.
Chemical Reviews,
Journal Year:
2024,
Volume and Issue:
124(12), P. 7976 - 8008
Published: May 27, 2024
Transfer
ribonucleic
acid
(tRNA)
therapeutics
will
provide
personalized
and
mutation
specific
medicines
to
treat
human
genetic
diseases
for
which
no
cures
currently
exist.
The
tRNAs
are
a
family
of
adaptor
molecules
that
interpret
the
nucleic
sequences
in
our
genes
into
amino
proteins
dictate
cell
function.
Humans
encode
more
than
600
tRNA
genes.
Interestingly,
even
healthy
individuals
contain
some
mutant
make
mistakes.
Missense
suppressor
insert
wrong
proteins,
nonsense
read
through
premature
stop
signals
generate
full
length
proteins.
Mutations
underlie
many
diseases,
including
neurodegenerative
cancers,
diverse
rare
disorders,
result
from
missense
or
mutations.
Thus,
variants
can
be
strategically
deployed
as
therapeutic
agents
correct
defects.
We
review
mechanisms
activity,
nature
window
suppression
well
wild-type
supplementation.
discuss
challenges
promises
delivering
synthetic
RNAs
gene
therapies.
Together,
novel
treatments
common
humans.
