Nature Communications,
Год журнала:
2020,
Номер
11(1)
Опубликована: Июль 3, 2020
Abstract
Expansion
of
an
intronic
(GGGGCC)
n
repeat
region
within
the
C9orf72
gene
is
a
main
cause
familial
amyotrophic
lateral
sclerosis
and
frontotemporal
dementia
(c9ALS/FTD).
A
hallmark
c9ALS/FTD
accumulation
misprocessed
RNAs,
which
are
often
targets
cellular
RNA
surveillance.
Here,
we
show
that
decay
mechanisms
involving
upstream
frameshift
1
(UPF1),
including
nonsense-mediated
(NMD),
inhibited
in
brains
cultured
cells
expressing
either
two
arginine-rich
dipeptide
repeats
(R-DPRs),
poly(GR)
poly(PR).
Mechanistically,
although
R-DPRs
recruitment
UPF1
to
stress
granules,
granule
formation
independent
NMD
inhibition.
Instead,
inhibition
primarily
result
from
global
translational
repression
caused
by
R-DPRs.
Overexpression
UPF1,
but
none
its
NMD-deficient
mutants,
enhanced
survival
neurons
treated
R-DPRs,
suggesting
neurotoxicity
part
inhibiting
Nonsense-mediated
mRNA
decay
(NMD),
which
is
arguably
the
best-characterized
translation-dependent
regulatory
pathway
in
mammals,
selectively
degrades
mRNAs
as
a
means
of
post-transcriptional
gene
control.
Control
can
be
for
purpose
ensuring
quality
expression.
Alternatively,
control
facilitate
adaptation
cells
to
changes
their
environment.
The
key
NMD,
no
matter
what
its
purpose,
ATP-dependent
RNA
helicase
upstream
frameshift
1
(UPF1),
without
NMD
fails
occur.
However,
UPF1
does
much
more
than
regulate
NMD.
As
examples,
engaged
functionally
diverse
pathways
mediated
by
variety
RNA-binding
proteins
that
include
staufen,
stem–loop-binding
protein,
glucocorticoid
receptor,
and
regnase
1.
Moreover,
promotes
tudor-staphylococcal/micrococcal-like
nuclease-mediated
microRNA
decay.
In
this
review,
we
first
focus
on
how
machinery
recognizes
an
target
triggers
degradation.
Next,
compare
contrast
mechanisms
functions
other
also
UPF1,
protein
polymath,
engenders
with
ability
shape
transcriptome
response
biological
physiological
needs.
Stop
codon
readthrough
(SCR)
occurs
when
the
ribosome
miscodes
at
a
stop
codon.
Such
events
can
be
therapeutically
desirable
premature
termination
(PTC)
is
found
in
critical
gene.
To
study
SCR
vivo
genome-wide
manner,
we
treated
mammalian
cells
with
aminoglycosides
and
performed
profiling.
We
find
that
addition
to
stimulating
of
PTCs,
stimulate
normal
codons
(NTCs)
genome-wide.
identity,
nucleotide
following
codon,
surrounding
mRNA
sequence
context
all
influence
likelihood
SCR.
In
comparison
NTCs,
downstream
3'UTRs
are
recognized
less
efficiently
by
ribosomes,
suggesting
targeting
for
may
achievable
without
general
disruption
translation
termination.
Finally,
G418-induced
miscoding
alters
gene
expression
substantial
effects
on
histone
genes,
selenoprotein
S-adenosylmethionine
decarboxylase
(AMD1).Many
genes
provide
set
instructions
needed
build
protein,
which
read
structures
called
ribosomes
through
process
translation.
The
genetic
information
contains
short,
coded
instruction
marks
end
protein.
When
finds
it
should
building
release
protein
has
made.
Ribosomes
do
not
always
codons.
Certain
chemicals
actually
prevent
from
detecting
correctly,
drugs
have
exactly
this
effect.
Aminoglycosides
used
as
antibiotics
low
doses
because
they
interfere
bacteria,
but
higher
also
human
cells.
readthrough.
There
different
types
some
naturally
more
effective
stopping
than
others.
Wangen
Green
now
examined
effect
an
aminoglycoside
G418
grown
laboratory.
results
showed
how
interacted
revealed
certain
affected
other
sequences
around
affect
encourage
common
area
These
findings
highlight
evolutionary
pressure
driving
develop
strong
resist
Despite
this,
still
like
Some
conditions,
cystic
fibrosis,
result
incorrect
genes.
Drugs
promote
specifically
these
could
useful
new
treatments.
RNA
polymerase
II
(RNA
Pol
II)
speed
or
elongation
rate,
i.e.,
the
number
of
nucleotides
synthesized
per
unit
time,
is
a
major
determinant
transcriptome
composition.
It
controls
co-transcriptional
processes
such
as
splicing,
polyadenylation,
and
transcription
termination,
thus
regulating
production
alternative
splice
variants,
circular
RNAs,
alternatively
polyadenylated
transcripts,
read-through
transcripts.
itself
regulated
in
response
to
intra-
extra-cellular
stimuli
can
turn
affect
composition
these
stimuli.
Evidence
points
potentially
important
role
modification
through
regulation
for
adaptation
cells
changing
environment,
pointing
function
cellular
physiology.
Analyzing
dynamics
may
therefore
be
central
fully
understand
physiological
processes,
development
multicellular
organisms.
Recent
findings
also
raise
possibility
that
deregulation
detrimental
participate
disease
progression.
Here,
we
review
initial
current
approaches
measure
speed,
well
providing
an
overview
factors
controlling
which
are
affected.
Finally,
discuss
cell
Metabolites
such
as
crotonyl-CoA
and
lactyl-CoA
influence
gene
expression
by
covalently
modifying
histones,
known
histone
lysine
crotonylation
(Kcr)
lactylation
(Kla).
However,
the
existence
patterns,
dynamic
changes,
biological
functions
associations
of
these
modifications
with
acetylation
during
mammalian
development
remain
largely
unknown.
Here,
we
find
that
Kcr
Kla
are
widely
distributed
in
brain
undergo
global
changes
neural
development.
By
profiling
genome-wide
dynamics
H3K9ac,
H3K9cr
H3K18la
combination
ATAC
RNA
sequencing,
reveal
marks
tightly
correlated
chromatin
state
expression,
extensively
involved
transcriptome
remodeling
to
promote
cell-fate
transitions
developing
telencephalon.
Importantly,
demonstrate
levels
not
consequence
transcription
identify
deacetylases
(HDACs)
1-3
novel
'erasers'
H3K18la.
Using
P19
cells
an
induced
differentiation
system,
HDAC1-3
inhibition
MS-275
pre-activates
neuronal
transcriptional
programs
stimulating
multiple
acylations
simultaneously.
These
findings
suggest
play
crucial
roles
epigenetic
regulation
Science,
Год журнала:
2019,
Номер
367(6473), С. 100 - 104
Опубликована: Ноя. 15, 2019
Tubulins
play
crucial
roles
in
cell
division,
intracellular
traffic,
and
shape.
Tubulin
concentration
is
autoregulated
by
feedback
control
of
messenger
RNA
(mRNA)
degradation
via
an
unknown
mechanism.
We
identified
tetratricopeptide
protein
5
(TTC5)
as
a
tubulin-specific
ribosome-associating
factor
that
triggers
cotranslational
tubulin
mRNAs
response
to
excess
soluble
tubulin.
Structural
analysis
revealed
TTC5
binds
near
the
ribosome
exit
tunnel
engages
amino
terminus
nascent
tubulins.
mutants
incapable
or
interaction
abolished
autoregulation
showed
chromosome
segregation
defects
during
mitosis.
Our
findings
show
how
subset
can
be
targeted
for
coordinated
specificity
recognizes
polypeptides
they
encode.
