bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2022,
Номер
unknown
Опубликована: Ноя. 5, 2022
Abstract
Cancer
has
been
characterized
as
a
wound
that
does
not
heal.
Malignant
cells
are
morphologically
distinct
from
normal
proliferating
cells,
but
have
extensive
similarities
to
tissues
undergoing
healing
and/or
regeneration.
The
mechanistic
basis
of
this
similarity
has,
however,
remained
enigmatic.
Here
we
show
the
genomic
region
upstream
Myc,
which
is
required
for
intestinal
tumorigenesis,
also
regeneration
after
radiation
damage.
critical
growth
adult
in
3D
organoid
culture,
indicating
culture
conditions
recapitulate
most
aspects
tissue
architecture
still
reprogram
proliferate
using
mechanism
similar
employed
by
cancer
cells.
Our
results
uncover
genetic
link
between
and
establish
renewal
severe
damage
mechanistically
distinct.
Summary
Myc
regulatory
links
Molecular Cell,
Год журнала:
2024,
Номер
84(2), С. 261 - 276.e18
Опубликована: Янв. 1, 2024
A
hallmark
of
high-risk
childhood
medulloblastoma
is
the
dysregulation
RNA
translation.
Currently,
it
unknown
whether
dysregulates
translation
putatively
oncogenic
non-canonical
open
reading
frames
(ORFs).
To
address
this
question,
we
performed
ribosome
profiling
32
tissues
and
cell
lines
observed
widespread
ORF
We
then
developed
a
stepwise
approach
using
multiple
CRISPR-Cas9
screens
to
elucidate
ORFs
putative
microproteins
implicated
in
survival.
determined
that
lncRNA-ORFs
upstream
(uORFs)
exhibited
selective
functionality
independent
main
coding
sequences.
microprotein
encoded
by
one
these
ORFs,
ASNSD1-uORF
or
ASDURF,
was
upregulated,
associated
with
MYC-family
oncogenes,
promoted
survival
through
engagement
prefoldin-like
chaperone
complex.
Our
findings
underscore
fundamental
importance
provide
rationale
include
future
studies
seeking
define
new
cancer
targets.
Frontiers in Cell and Developmental Biology,
Год журнала:
2024,
Номер
12
Опубликована: Март 6, 2024
MYC
is
a
pleiotropic
transcription
factor
involved
in
multiple
cellular
processes.
While
its
mechanism
of
action
and
targets
are
not
completely
elucidated,
it
has
fundamental
role
proliferation,
differentiation,
metabolism,
ribogenesis,
bone
vascular
development.
Over
4
decades
research
some
10,000
publications
linking
to
tumorigenesis
(by
searching
PubMed
for
“MYC
oncogene”)
have
led
becoming
most-wanted
target
the
treatment
cancer,
where
many
MYC’s
physiological
functions
become
co-opted
tumour
initiation
maintenance.
In
this
context,
an
abundance
reviews
describes
strategies
potentially
targeting
oncology
field.
However,
roles
different
aspects
biology
suggest
that
may
also
play
additional
diseases,
other
indeed
pathologies
beyond
cancer.
Here,
we
review
these
current
literature
non-oncological
diseases.
The
intense
efforts
towards
developing
inhibitors
as
cancer
therapy
will
huge
implications
addition,
with
complementary
approach,
discuss
diseases
conditions
appears
protective
hence
increased
expression
or
activation
could
be
therapeutic.
Clinical & Experimental Metastasis,
Год журнала:
2024,
Номер
41(6), С. 829 - 842
Опубликована: Авг. 20, 2024
Multiple
myeloma
(MM)
is
a
clinical
disorder
characterized
by
aberrant
plasma
cell
growth
in
the
bone
marrow
microenvironment.
Globally,
prevalence
of
MM
has
been
steadily
increasing
at
an
alarming
rate.
In
United
States,
more
than
30,000
cases
will
be
diagnosed
2024
and
it
accounts
for
about
2%
cancer
diagnoses
deaths,
double
worldwide
figure.
Both
symptomatic
active
are
distinguished
uncontrolled
growth,
which
results
severe
renal
impairment,
anemia,
hypercalcemia,
loss.
drugs
have
approved
FDA
now
widely
used
practice
MM.
Although
triplet
quadruplet
induction
regimens,
autologous
stem
transplantation
(ASCT),
maintenance
treatment
used,
continues
to
incurable
illness
relapses
that
may
occur
various
phases
its
progression.
patients
with
frailty,
extramedullary
disease,
leukemia,
central
nervous
system
recurrence,
functional
high
risk,
elderly
among
those
greatest
current
unmet
needs.
The
cost
care
additional
challenge.
cells
highly
protein
secretary
thus
dependent
on
activation
certain
translation
pathways.
also
chance
altering
ribosomal
protein-encoding
genes
like
MYC
mutation.
this
article
we
discuss
importance
ribosome
biogenesis
promoting
RNA
polymerase
I
inhibition
as
upcoming
potential
promise
patients.
Life Science Alliance,
Год журнала:
2025,
Номер
8(6), С. e202403090 - e202403090
Опубликована: Апрель 3, 2025
Cancer
has
been
characterized
as
a
wound
that
does
not
heal.
Malignant
cells
are
morphologically
distinct
from
normal
proliferating
but
have
extensive
similarities
to
tissues
undergoing
healing
and/or
regeneration.
The
mechanistic
basis
of
this
similarity
has,
however,
remained
enigmatic.
Here,
we
show
the
genomic
region
upstream
Myc
,
which
carries
more
cancer
susceptibility
in
humans
than
any
other
region,
is
required
for
intestinal
regeneration
after
radiation
damage.
Failure
regenerate
associated
with
inefficient
Ly6a
/Sca1
+
stem/progenitor
cell
mobilization,
and
almost
complete
failure
re-establish
Lgr5+
compartment
crypts.
also
critical
growth
adult
3D
organoid
culture.
We
culture
conditions
recapitulating
most
aspects
tissue
architecture
still
reprogram
proliferate
using
mechanism
similar
employed
by
cells.
Our
results
establish
function
2-540
super-enhancer
genetic
link
between
tumorigenesis,
demonstrates
renewal
severe
damage
mechanistically
distinct.
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Фев. 29, 2024
Demand-adjusted
and
cell
type
specific
rates
of
protein
synthesis
represent
an
important
safeguard
for
fate
function
long-term
hematopoietic
stem
cells.
Here,
we
identify
increased
in
the
fetal
pool
at
onset
failure
Fanconi
Anemia,
a
prototypical
DNA
repair
disorder
that
manifests
with
bone
marrow
failure.
Mechanistically,
accumulation
misfolded
proteins
Fancd2
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2023,
Номер
unknown
Опубликована: Май 6, 2023
Summary
A
hallmark
of
high-risk
childhood
medulloblastoma
is
the
dysregulation
RNA
translation.
Currently,
it
unknown
whether
dysregulates
translation
putatively
oncogenic
non-canonical
open
reading
frames.
To
address
this
question,
we
performed
ribosome
profiling
32
tissues
and
cell
lines
observed
widespread
ORF
We
then
developed
a
step-wise
approach
to
employ
multiple
CRISPR-Cas9
screens
elucidate
functional
ORFs
implicated
in
survival.
determined
that
lncRNA-ORFs
upstream
frames
(uORFs)
exhibited
selective
functionality
independent
main
coding
sequence.
One
these,
ASNSD1-uORF
or
ASDURF,
was
upregulated,
associated
with
MYC
family
oncogenes,
required
for
survival
through
engagement
prefoldin-like
chaperone
complex.
Our
findings
underscore
fundamental
importance
provide
rationale
include
these
future
cancer
genomics
studies
seeking
define
new
targets.
Highlights
Ribo-seq
reveals
High-resolution
CRISPR
tiling
uORF
functions
controls
downstream
pathways
complex
necessary
Nature Biotechnology,
Год журнала:
2022,
Номер
41(2), С. 197 - 203
Опубликована: Сен. 26, 2022
Abstract
Here
we
describe
a
competitive
genome
editing
method
that
measures
the
effect
of
mutations
on
molecular
functions,
based
precision
CRISPR
using
template
libraries
with
either
original
or
altered
sequence,
and
sequence
tag,
enabling
direct
comparison
between
mutated
cells.
Using
example
MYC
oncogene,
identify
important
transcriptional
targets
show
E-box
at
target
gene
promoters
reduce
cellular
fitness.
Cell Reports,
Год журнала:
2023,
Номер
42(7), С. 112739 - 112739
Опубликована: Июль 1, 2023
The
ability
to
feed
on
a
sugar-containing
diet
depends
gene
regulatory
network
controlled
by
the
intracellular
sugar
sensor
Mondo/ChREBP-Mlx,
which
remains
insufficiently
characterized.
Here,
we
present
genome-wide
temporal
clustering
of
sugar-responsive
expression
in
Drosophila
larvae.
We
identify
programs
responding
feeding,
including
downregulation
ribosome
biogenesis
genes,
known
targets
Myc.
Clockwork
orange
(CWO),
component
circadian
clock,
is
found
be
mediator
this
repressive
response
and
necessary
for
survival
high-sugar
diet.
CWO
directly
activated
Mondo-Mlx,
it
counteracts
Myc
through
repression
its
binding
overlapping
genomic
regions.
mouse
ortholog
BHLHE41
has
conserved
role
repressing
genes
primary
hepatocytes.
Collectively,
our
data
uncover
cross-talk
between
circuits
balancing
activities
anabolic
pathways
maintain
homeostasis
during
feeding.
Frontiers in Cell and Developmental Biology,
Год журнала:
2023,
Номер
11
Опубликована: Дек. 28, 2023
The
nucleolus
is
a
subnuclear
compartment
critical
in
ribosome
biogenesis
and
cellular
stress
responses.
These
mechanisms
are
governed
by
complex
interplay
of
proteins,
including
NOC1,
member
the
NOC
family
nucleolar
proteins
responsible
for
controlling
rRNA
processing
ribosomal
maturation.
This
study
reveals
novel
relationship
between
NOC1
MYC
transcription
factor,
known
its
crucial
role
biogenesis,
cell
growth,
proliferation.
Here,
we
demonstrate
that
functions
as
direct
target
MYC,
it
transcriptionally
induced
through
functional
MYC-binding
E-box
sequence
promoter
region.
Furthermore,
protein
interactome
analysis
NOC1-complex
includes
NOC2
NOC3
other
components
such
Nucleostemin1
Ns1
transporters
subunits
involved
In
response
to
expression
localization
within
significantly
increase,
suggesting
link
activity
function.
Notably,
over-expression
leads
formation
large
nuclear
granules
enlarged
nucleoli,
which
co-localize
with
fibrillarin
Ns1.
Additionally,
necessary
localization,
maintaining
structure.
Finally,
co-expression
enhances
size
maintains
their
co-localization,
outlining
another
aspect
cooperation
dynamics.
also
an
enrichment
few
RNA
processing,
modification,
splicing.
Moreover,
Ythdc1,
Flacc,
splenito
mediate
N6-methyladenosine
(m6A)
methylation
mRNAs
export,
revealing
NOC1’s
potential
involvement
coordinating
splicing
mRNA
export.
summary,
uncovered
roles
homeostasis
established
connection
network
governing
structure
findings
highlight
interaction
relevant
specific
functions,
broader
addition
control
providing
new
insight
can
be
further
investigated.
