G3 Genes Genomes Genetics,
Год журнала:
2025,
Номер
unknown
Опубликована: Фев. 14, 2025
Abstract
The
Mediator
complex
coordinates
regulatory
input
for
transcription
driven
by
RNA
polymerase
II
in
eukaryotes.
reduced
epidermal
fluorescence4-3
(ref4-3)
is
a
semidominant
mutation
that
results
single
amino
acid
substitution
the
tail
subunit
Med5b.
Previous
characterization
of
ref4-3
revealed
altered
expression
variety
loci
Arabidopsis,
including
those
contributing
to
phenylpropanoid
biosynthesis.
Examination
existing
RNA-seq
data
indicated
enriched
transcriptionally
repressive
chromatin
modification
H3K27me3
are
overrepresented
among
genes
misregulated
ref4-3.
We
used
ChIP-seq
and
examine
possibility
perturbation
homeostasis
plants
contributed
transcript
levels.
observed
modest
global
reduction
at
this
not
dependent
on
gene
expression;
however,
was
strongly
predictive
plants.
Instead,
our
analyses
substantial
enrichment
targets
MYC2
transcriptional
regulator
exhibit
decreased
Consistent
with
previous
ref4-3,
we
ref4-3-dependent
can
be
suppressed
loss
another
subunit,
MED25.
This
observation
consistent
biochemical
MYC2.
Our
highlight
diverse
distinct
impacts
change
have
circuits
raise
prospect
directly
contributes
Journal of Education Health and Sport,
Год журнала:
2022,
Номер
12(8), С. 730 - 926
Опубликована: Авг. 23, 2022
The
book
is
intended
for
students
studying
medical
and
biological
specialties.
CHAPTER
I.
EPIGENETICS
INTRODUCTION
science
of
epigenetics
looks
at
the
mechanisms
molecular
modifications
histones
DNA
that
can
regulate
gene
activity
without
affecting
nucleotide
sequences
in
molecule.
Recognized
epigenetic
regulators
are
methylation,
post-translational
histones,
non-coding
RNAs
(nkRNAs).
One
most
important
differences
between
eukaryotic
cells
prokaryotes
presence
a
complex
nucleo-protein
chromatin
eukaryotes.
It
this
form
molecule
stored
our
cells.
On
one
hand,
structural
organization
provides
compact
arrangement
cell
nucleus.
other
directly
involved
process
regulating
expression.
At
same
time,
nucleosome
depicted
Fig.
1
(a
functional
unit
chromatin)
considered
as
key
component
processes
nucleus
8
histone
proteins
(octamers).
consists
two
copies
each
H2A,
H2B,
H3
H4.
chain,
which
includes
147
nucleotides,
folds
1.65
times
around
octamer
histones.
nucleosomes
arranged
linear
array
along
"beads
on
string".
linker
section
connecting
adjacent
(transcriptionally
inactive)
sealed
with
H1-histone
protein.
length
30
nm.
Moreover,
site
beginning
transcription
usually
located
inside
nucleosome.
Consequently,
serves
repressor,
preventing
initiation
transcription.
That
is,
total
repression
genes.
In
contrast,
becomes
possible
result
remodeling
factors
enable
"dismantling"
or
otherwise
alter
their
structure
organization.
Thus,
(inactivation)
genes
begins
wrapping
nucleosome,
liberation
from
(activation)
involves
freeing
binding
to
unfolding
by
(Lorch
Y.,
Kornberg
R.
D.,
2017).
Thanks
mechanism,
selective
expression
only
those
needed
given
time
tissue
possible.
should
be
emphasized
extends
not
transcription,
but
also
associated
molecule,
such
replication,
mitotic
division,
repair
double-strand
breaks,
maintenance
telomeres.
control
various
physiological
pathological
corresponding
changing
availability
systems
chromatin.
scope
application
research
methods
rapidly
expanding.
Currently,
we
witnessing
active
introduction
approaches
field
practical
medicine
aimed
diagnosing
treating
dangerous
human
diseases.
II.
TRANSCRIPTION
FACTORS
For
first
existence
was
revealed
basis
discovery
made
it
establish
vitro
purified
RNA
polymerase-II
initiate
template
extract
(Weil
P.
A.
et
al.,
1979).
Further
fractionation
identification
general
(GTF)
required
has
identified
similar
rats,
Drosophila,
yeast
substantiated
assumption
GTFs
indeed
"common"
necessary
transcribed
polymerase
highly
conserved
number
organisms
(Matsui
T.
1980).
We
mention
II
because
type
enzyme
ability
synthesize
mRNA.
Whereas
I
responsible
synthesis
pro-rRNA,
III
tRNA
RNAs.
Meanwhile,
regulation
eukaryotes
quite
complex,
since
depends
complexes
(Burns
L.
G.,
Peterson
C.
L.,
1997)
covalent
modification
(Natsume-Kitatani
Mamitsuka
H.,
2016).
initiation,
immediate
target
GTF
well-defined
promo
zone
gene.
promotra
eukaryotes,
main
elements
regulatory
distinguished.
(bark
promoter,
see
2.1)
attributed
assembling
(PIC),
including
TATA
sequence
above
start
(TSS
),
an
initiating
(Inr)
covering
site.
Promoters
may
include
unit,
initiator
(Inr),
both
(Hampsey
M.,
1998).
A
third
major
element,
downstream
promoter
element
(DPE),
originally
described
Drosophila
about
p.p.
below
TSS.
DPE
appears
function
conjunction
Inr
factor
TFIID
non-TATA
promoters.
According
current
research,
cellular
(main)
promoters
multicellular
contain
short
nucleotides
called
cow
(motifs)
(e.g.,
block,
lower
(DPE))
recruit
through
common
mechanism
(Dreos
2021).
authors
report
classes
Inr+DPE
present
genome
humans
structurally
other,
different
species
organisms.
studied
box,
box
found
10-20%
cortical
Therefore,
sequence,
name
known
elements,
include:
BRE,
MTE,
TST
sequences.
BRE
(TFIIB
recognition
element)
motifs
either
(BREu)
(BREd)
box.
TBP,
demonstrate
high
levels
conservatism
range
archaebacteria
(Kadonaga
J.
T.,
2012).
doing
so,
BREu
well
BREd
have
positive
negative
effects
activity.
core
(DPE)
detected
analysis
Drosophila.
MTE
(motif
ten
element),
front
DPE,
overrepresented
"motif
10"
then
discovered,
promoter.
exhibit
humans,
appear
recognized
subunits
TFIID,
TAF
resemble
structure.
turn,
TCT
regulates
ribosomal
protein
humans.
Although
there
no
universal
all
promoters,
concept
nuclear
defined
minimum
stretch
sufficient
accurately
2012;
Haberle
V.,
Stark
A.,
2018).
noted
results
modern
will
constantly
supplement
list
new
components
example,
DNA-replicatedrelated
(DRE),
Ohler
1,6
7
(Danino
Y.
M.
2015;
authors,
bark
transformed
course
evolution.
Due
this,
modulated
composition
elements.
Such
modulation
achieved
emergence
combinations
additional
level
realized.
To
summarize
facts,
initiated
specific
position,
Transcription
Initiation
Site
(TSS),
5'
end
TSS
embedded
spanning
50
base
pairs
platform
related
(GTFs).
Regulatory
low
basal
activity,
further
activated,
generally
more
distally
enhancers
(discussed
below).
Enhancers
bind
factors,
cofactors,
enhance
III.
CELL
SIGNALING
PATHWAYS
organism,
work
regulated
large
signals.
These
signals
formed
organism
itself,
reflecting
needs
living
(metabolic
state,
stages
development,
differentiation,
reproduction),
reaction
external
environment.
implementation
these
encompasses
biochemical
lead
cell's
perception
signal
response.
something
receptor,
turn
response
signal.
receptor
recognizes
signal,
interprets
specificity
translates
into
intracellular
signaling
molecules,
cascade
phosphorylation,
pathways.
soon
(ligand)
binds
its
–
complementary
transmembrane
cell.
Growth
hormones,
cytokines,
neurotransmitters,
extracellular
matrix,
etc.
chemical
nature
ligands
diverse,
small
molecules
lipids
(prostaglandins,
steroid
hormones),
(for
peptide
cytokines
chemokines,
growth
factors).,
polymers
sugars
β-glucan
zymosan)
proteoglycans),
nucleic
acids,
Binding
ligand
induces
conformational
changes
translated
activating
cascades
secondary
messengers
(kinases,
phosphatases,
GTPases,
ions
cAMP,
cGMP,
diacylglycerol,
etc.).
message
transmitted
membrane
nucleus,
where
expression,
subsequent
translation
targeting
organelles
triggered.
There
types
receptors
(transmembrane)
receptors.
Membrane
plasma
separate
domain
ligand,
hydrophobic
nature,
cytoplasmic
domain.
Cell
surface
divided
G-protein-bound
receptors,
tyrosine
kinase-bound
ionotropic
When
binds,
undergo
activate
enzymatic
domain,
kinases,
phosphatases
adapter
proteins.
covalently
bound
capable
producing
transmission.
Intracellular
(estrogen
glucocorticoid
progesterone
retinoic
acid
thyroid
hormone
etc.),
membranes
(mitochondria,
endoplasmic
reticulum
Golgi
apparatus).
information
received
receptor)
targets.
All
path
transmission
However,
certain
set
effector
proteins,
enzymes
substrates
implement
pathway
(signaling
cascade).
Recently,
however,
been
growing
evidence
themselves
play
extremely
role
signaling,
theso-called
scaffold
("platform
proteins",
adaptor
proteins),
coordinate
assembly
multicomponent
complexes.
Scaffold
several
single
thereby
modulating
efficiency
bringing
closer
together,
direct
flow
cell,
activating,
coordinating
events
networks
(Skovorodnikova
P.A.
literature,
described,
cover
wide
functions.
This
group
three
categories
(Fig.
1):
simple
functionally
dependent
(adaptors),
larger
multi-domain
designed
(scaffold⁄anchoring
proteins)
specialized
localizing
proteins-components
pathways
(docking
(
Buday
Tompa
P,
2010)
platforms
increases
selectivity
pathway,
allows
formation
feedback.
e
ultimate
ultimately
allow
resulting
converted
change
(Brivanlou
Darnell
E.,
2002).
Most
eventually
activation
repressors
sequence.
Eukaryotic
like
takes
place
cytoplasm.
Signal
multifactorial
system,
based
nodular
special
cascades.
none
isolation.
interaction
inevitable
complexes,
when
system
perceives
combination
stimuli
(hormones,
pathogenic
ligands),
preserves
accuracy
(Saini
N.,
Sarin
relatively
development
mammals
Combinations
action
determine
decisions
fate
differentiation
ontogenesis
(Li
R.,
Elowitz
M.V.,
2019;
de
Roo
Staal
F.
2020)
malignancy
(Dreesen
O.,
Brivanlou
A.N.,
2007;
Skovorodnikova
Consider
some
medically
important.
IV.
MOLECULAR
BIOLOGY
OF
THE
TUMOR:
MECHANISMS
INITIATION,
PROMOTION
AND
PROGRESSION
Tumor
diseases
occupy
leading
place,
terms
morbidity
mortality.
despite
advances
study
genetic
patterns,
many
unresolved
questions
remain.
spectrum
markers
makes
diagnose,
predict
course,
degree
malignancy,
rate
tumor
progression
therapy.
occur
characterized
stability,
they
dynamic
profile
-
appearance
clones
properties.
heterogeneity
simultaneously
complicates
strategy
managing
patients,
creating
prerequisites
characteristics
Nucleic Acids Research,
Год журнала:
2023,
Номер
51(14), С. 7288 - 7313
Опубликована: Июнь 28, 2023
Abstract
We
have
conducted
a
detailed
transcriptomic,
proteomic
and
phosphoproteomic
analysis
of
CDK8
its
paralog
CDK19,
alternative
enzymatic
components
the
kinase
module
associated
with
transcriptional
Mediator
complex
implicated
in
development
diseases.
This
was
performed
using
genetic
modifications
selective
CDK8/19
small
molecule
inhibitors
potent
PROTAC
degrader.
inhibition
cells
exposed
to
serum
or
agonists
NFκB
protein
C
(PKC)
reduced
induction
signal-responsive
genes,
indicating
pleiotropic
role
kinases
signal-induced
reprogramming.
under
basal
conditions
initially
downregulated
group
most
which
were
inducible
by
PKC
stimulation.
Prolonged
mutagenesis
upregulated
larger
gene
set,
along
post-transcriptional
increase
proteins
comprising
core
module.
Regulation
both
RNA
expression
required
activities
but
enzymes
protected
their
binding
partner
cyclin
from
proteolytic
degradation
kinase-independent
manner.
Analysis
isogenic
cell
populations
expressing
CDK8,
CDK19
kinase-inactive
mutants
revealed
that
same
qualitative
effects
on
phosphorylation
at
levels,
whereas
differential
versus
knockouts
attributable
quantitative
differences
activity
rather
than
different
functions.
Journal of Clinical Investigation,
Год журнала:
2024,
Номер
134(10)
Опубликована: Март 28, 2024
Mediator
kinases
CDK19
and
CDK8,
pleiotropic
regulators
of
transcriptional
reprogramming,
are
differentially
regulated
by
androgen
signaling
but
both
upregulated
in
castration-resistant
prostate
cancer
(CRPC).
Genetic
or
pharmacological
inhibition
CDK8
reverses
the
phenotype
restores
sensitivity
CRPC
xenografts
to
deprivation
vivo.
Prolonged
CDK8/19
inhibitor
treatment
combined
with
castration
not
only
suppresses
growth
also
induces
tumor
regression
cures.
Transcriptomic
analysis
revealed
that
kinase
amplifies
modulates
effects
on
gene
expression,
disrupting
adaptation
deprivation.
inactivation
cells
affects
stromal
indicating
activity
molds
microenvironment.
The
combination
downregulates
MYC
pathway,
a
MYC-driven
model
even
without
castration.
inhibitors
show
efficacy
patient-derived
xenograft
models
CRPC,
signature
correlates
progression
overall
survival
clinical
samples
metastatic
CRPC.
These
results
indicate
mediate
androgen-independent
vivo
supporting
development
for
this
presently
incurable
disease.
The EMBO Journal,
Год журнала:
2024,
Номер
43(3), С. 437 - 461
Опубликована: Янв. 16, 2024
Abstract
Plants
are
often
exposed
to
recurring
adverse
environmental
conditions
in
the
wild.
Acclimation
high
temperatures
entails
transcriptional
responses,
which
prime
plants
better
withstand
subsequent
stress
events.
Heat
(HS)-induced
memory
results
more
efficient
re-induction
of
transcription
upon
recurrence
heat
stress.
Here,
we
identified
CDK8
and
MED12,
two
subunits
kinase
module
co-regulator
complex,
Mediator,
as
promoters
associated
histone
modifications
Arabidopsis.
is
recruited
heat-stress
genes
by
HEAT
SHOCK
TRANSCRIPTION
FACTOR
A2
(HSFA2).
Like
HSFA2,
largely
dispensable
for
initial
gene
induction
HS,
its
function
thus
independent
primary
activation.
In
addition
promoter
start
region
target
genes,
also
binds
their
3ʹ-region,
where
it
may
promote
elongation,
termination,
or
rapid
re-initiation
RNA
polymerase
II
(Pol
II)
complexes
during
bursts.
Our
work
presents
a
complex
role
Mediator
multicellular
eukaryotes,
through
interactions
with
factors,
chromatin
modifications,
promotion
Pol
efficiency.
International Journal of Molecular Sciences,
Год журнала:
2023,
Номер
24(3), С. 2855 - 2855
Опубликована: Фев. 2, 2023
In
higher
eukaryotes,
the
regulation
of
developmental
gene
expression
is
determined
by
enhancers,
which
are
often
located
at
a
large
distance
from
promoters
they
regulate.
Therefore,
architecture
chromosomes
and
mechanisms
that
determine
functional
interaction
between
enhancers
decisive
importance
in
development
organisms.
Mammals
model
animal
Drosophila
have
homologous
key
architectural
proteins
similar
organization
chromosome
architecture.
This
review
describes
current
progress
understanding
formation
long-range
interactions
three
well-studied
regulatory
loci
Drosophila.
Abstract
Prostate
cancer
progression
is
driven
by
androgen
receptor
(AR)
activity,
which
a
target
for
therapeutic
approaches.
Enzalutamide
an
AR
inhibitor
that
prolongs
the
survival
of
patients
with
advanced
prostate
cancer.
However,
resistance
mechanisms
arise
and
impair
its
efficacy.
One
these
expression
AR-V7,
constitutively
active
splice
variant.
The
Mediator
complex
multisubunit
protein
modulates
gene
on
genome-wide
scale.
MED12
cyclin-dependent
kinase
(CDK)8,
or
paralog
CDK19,
are
components
module
regulates
proliferation
cells.
In
this
study,
we
investigated
how
CDK8/19
influence
cancer-driven
processes
in
cell
lines,
focusing
activity
enzalutamide
response.
We
inhibited
LNCaP
(AR+,
enzalutamide-sensitive),
22Rv1
(AR-V7+,
enzalutamide-resistant),
PC3
(AR−,
enzalutamide-insensitive)
Both
inhibition
reduced
all
respective
3D
spheroids.
knockdown
significantly
c-Myc
signaling
pathways.
cells,
it
consistently
response,
prostate-specific
antigen
(PSA)
secretion,
genes,
AR-V7
expression.
Combined
enzalutamide,
additively
decreased
both
PSA
secretion
cells
and,
when
combined
Our
study
revealed
regulate
their
may
modulate
response
to
Unlike
most
species
that
use
telomerase
for
telomere
maintenance,
many
dipterans,
including
Drosophila
,
rely
on
three
telomere-specific
retrotransposons
(TRs)—
HeT-A
TART
and
TAHRE
—to
form
tandem
repeats
at
chromosome
ends.
Although
TR
transcription
is
crucial
in
their
life
cycle,
its
regulation
remains
poorly
understood.
This
study
identifies
the
Mediator
complex,
E2F1-Dp,
Scalloped/dTEAD
as
key
regulators
of
transcription.
Reducing
activity
or
Sd/dTEAD
increases
expression
length,
while
overexpressing
E2F1-Dp
depleting
Rbf1
stimulates
The
regulate
this
process
through
E2F1-Dp.
CUT&RUN
(Cleavage
under
targets
release
using
nuclease)
analysis
shows
direct
binding
CDK8,
Dp,
to
telomeric
repeats,
with
motif
enrichment
revealing
E2F-
TEAD-binding
sites.
These
findings
uncover
complex’s
role
controlling
length
Sd,
coupling
transcriptional
cycle
host
cell-cycle
machinery
protect
ends
.
Hyperactive
interferon
(IFN)
signaling
is
a
hallmark
of
Down
syndrome
(DS),
condition
caused
by
Trisomy
21
(T21);
strategies
that
normalize
IFN
could
benefit
this
population.
Mediator-associated
kinases
CDK8
and
CDK19
drive
inflammatory
responses
through
incompletely
understood
mechanisms.
Using
sibling-matched
cell
lines
with/without
T21,
we
investigated
Mediator
kinase
function
in
the
context
hyperactive
DS
over
75
min
to
24
hr
timeframe.
Activation
IFN-response
genes
was
suppressed
cells
treated
with
CDK8/CDK19
inhibitor
cortistatin
A
(CA),
via
rapid
suppression
IFN-responsive
transcription
factor
(TF)
activity.
We
also
discovered
affect
splicing,
novel
means
which
control
gene
expression.
To
further
probe
function,
completed
cytokine
screens
metabolomics
experiments.
Cytokines
are
master
regulators
responses;
screening
105
different
proteins,
show
help
IFN-dependent
at
least
part
transcriptional
regulation
receptors.
Metabolomics
revealed
inhibition
altered
core
metabolic
pathways
type-specific
ways,
broad
upregulation
anti-inflammatory
lipid
mediators
occurred
specifically
kinase-inhibited
during
IFNγ
signaling.
subset
these
lipids
(e.g.
oleamide,
desmosterol)
serve
as
ligands
for
nuclear
receptors
PPAR
LXR,
activation
CA-treated
cells,
revealing
mechanistic
links
between
kinases,
metabolism,
receptor
function.
Collectively,
our
results
establish
context-specific
regulators,
reveal
expression
not
only
TFs,
but
changes
splicing.
Moreover,
antagonizes
transcriptional,
metabolic,
responses,
implications
other
chronic
conditions.
Current Opinion in Chemical Biology,
Год журнала:
2022,
Номер
70, С. 102186 - 102186
Опубликована: Авг. 1, 2022
Transcription
by
RNA
polymerase
II
(pol
II)
is
regulated
kinases.
In
recent
years,
many
selective
and
potent
inhibitors
of
pol
transcription-associated
kinases
have
been
developed,
these
molecules
advanced
understanding
kinase
function
in
mammalian
cells.
Here,
we
focus
on
chemical
the
CDK7,
CDK8,
CDK9,
CDK12,
CDK13,
CDK19.
We
provide
a
brief
overview
common
activation
mechanisms.
then
highlight
advantages
compared
with
other
basic
research
methods,
describe
caveats
associated
non-selective
compounds
(e.g.
flavopiridol).
conclude
strategies
recommendations
for
implementation
experimental
analysis
Wiley Interdisciplinary Reviews - RNA,
Год журнала:
2023,
Номер
15(1)
Опубликована: Сен. 17, 2023
Abstract
A
family
of
structurally
related
cyclin‐dependent
protein
kinases
(CDKs)
drives
many
aspects
eukaryotic
cell
function.
Much
the
literature
in
this
area
has
considered
individual
members
to
act
primarily
either
as
regulators
cycle,
context
which
CDKs
were
first
discovered,
or
transcription.
Until
recently,
CDK7
was
only
clear
example
a
CDK
that
functions
both
processes.
However,
new
data
points
several
“cell‐cycle”
having
important
roles
transcription
and
some
“transcriptional”
cycle‐related
targets.
For
example,
novel
have
been
demonstrated
for
archetypal
cycle
regulator
CDK1.
The
increasing
evidence
overlap
between
these
two
types
suggests
they
might
play
critical
role
coordinating
Here
we
review
canonical
cell‐cycle
transcriptional
CDKs,
provide
an
update
on
how
collaborate
perform
cellular
functions.
We
also
brief
overview
dysregulation
contributes
carcinogenesis,
possible
treatment
avenues.
This
article
is
categorized
under:
RNA
Interactions
with
Proteins
Other
Molecules
>
RNA‐Protein
Complexes
Processing
3′
End
Splicing
Regulation/Alternative