Proceedings of the National Academy of Sciences,
Год журнала:
2024,
Номер
122(1)
Опубликована: Дек. 31, 2024
Poly(ADP-ribose)
polymerase
1
(PARP1)
plays
a
crucial
role
in
DNA
repair
and
genomic
stability
maintenance.
However,
the
regulatory
mechanisms
governing
PARP1
activity,
particularly
through
deubiquitination,
remain
poorly
elucidated.
Using
deubiquitinase
(DUB)
library
binding
screen,
we
identified
cylindromatosis
(CYLD)
as
bona
fide
DUB
for
breast
cancer
cells.
Mechanistically,
CYLD
is
recruited
by
to
lesions
upon
genotoxic
stress,
where
it
cleaves
K63-linked
polyubiquitin
chains
on
at
residues
K748,
K940,
K949,
resulting
compromised
activation.
In
reciprocal
manner,
PARylates
sites
E191,
E231,
E259,
E509,
thereby
enhancing
its
activity.
Consequently,
depletion
of
leads
increased
efficiency
base
excision
confers
cells
with
resistance
alkylating
agents.
Conversely,
overexpression
enhances
sensitivity
PARP
inhibitors
(PARPi)
even
homologous
recombination-proficient
These
findings
offer
unique
insights
into
intricate
interplay
between
repair,
underscoring
pivotal
targeting
this
axis
chemotherapy.
Cell Communication and Signaling,
Год журнала:
2025,
Номер
23(1)
Опубликована: Март 18, 2025
Protein
quality
control
(PQC)
plays
a
vital
role
in
maintaining
normal
heart
function,
as
cardiomyocytes
are
relatively
sensitive
to
misfolded
or
damaged
proteins,
which
tend
accumulate
under
pathological
conditions.
Ubiquitin-specific
protease
(USP)
is
the
largest
deubiquitinating
enzyme
family
and
key
component
of
ubiquitin
proteasome
system
(UPS),
non-lysosomal
protein
degradation
machinery
mediate
PQC
cells.
USPs
regulate
stability
activity
target
proteins
that
involve
intracellular
signaling,
transcriptional
inflammation,
antioxidation,
cell
growth.
Recent
studies
demonstrate
can
fibrosis,
lipid
metabolism,
glucose
homeostasis,
hypertrophic
response,
post-ischemic
recovery
death
such
apoptosis
ferroptosis
cardiomyocytes.
Since
myocardial
loss
an
important
cardiomyopathy,
therefore,
these
findings
suggest
UPSs
play
emerging
roles
cardiomyopathy.
This
review
briefly
summarizes
recent
literature
on
regulatory
occurrence
development
giving
us
new
insights
into
molecular
mechanisms
different
cardiomyopathy
potential
preventive
strategies
for
Signal Transduction and Targeted Therapy,
Год журнала:
2024,
Номер
9(1)
Опубликована: Окт. 16, 2024
The
pathogenesis
of
doxorubicin-induced
cardiomyopathy
remains
unclear.
This
study
was
carried
out
to
test
our
hypothesis
that
ADAM17
aggravates
cardiomyocyte
apoptosis
induced
by
doxorubicin
and
inhibition
may
ameliorate
cardiomyopathy.
C57BL/6J
mice
were
intraperitoneally
injected
with
a
cumulative
dose
induce
Cardiomyocyte-specific
ADAM17-knockout
(A17
Biomolecules,
Год журнала:
2024,
Номер
14(5), С. 572 - 572
Опубликована: Май 12, 2024
The
balance
between
ubiquitination
and
deubiquitination
is
instrumental
in
the
regulation
of
protein
stability
maintenance
cellular
homeostasis.
deubiquitinating
enzyme,
ubiquitin-specific
protease
36
(USP36),
a
member
USP
family,
plays
crucial
role
this
dynamic
equilibrium
by
hydrolyzing
removing
ubiquitin
chains
from
target
proteins
facilitating
their
proteasome-dependent
degradation.
multifaceted
functions
USP36
have
been
implicated
various
disease
processes,
including
cancer,
infections,
inflammation,
via
modulation
numerous
events,
gene
transcription
regulation,
cell
cycle
immune
responses,
signal
transduction,
tumor
growth,
inflammatory
processes.
objective
review
to
provide
comprehensive
summary
current
state
research
on
roles
different
pathological
conditions.
By
synthesizing
findings
previous
studies,
we
aimed
increase
our
understanding
mechanisms
underlying
these
diseases
identify
potential
therapeutic
targets
for
treatment.
Journal of Xenobiotics,
Год журнала:
2025,
Номер
15(1), С. 9 - 9
Опубликована: Янв. 8, 2025
Chemotherapy-induced
cardiotoxicity
is
a
critical
issue
in
cardio-oncology,
as
cancer
treatments
often
lead
to
severe
cardiovascular
complications.
Approximately
10%
of
patients
succumb
problems,
with
lung
frequently
experiencing
arrhythmias,
cardiac
failure,
tamponade,
and
metastasis.
The
cardiotoxic
effects
anti-cancer
manifest
at
both
cellular
tissue
levels,
causing
deformation
cardiomyocytes,
leading
contractility
issues
fibrosis.
Repeated
irradiation
chemotherapy
increase
the
risk
valvular,
pericardial,
or
myocardial
diseases.
Multi-OMICs
analyses
reveal
that
targeting
specific
pathways
well
protein
modifications,
such
ubiquitination
phosphorylation,
could
offer
potential
therapeutic
alternatives
current
treatments,
including
Angiotensin
converting
enzymes
(ACE)
inhibitors
beta-blockers
mitigate
symptoms
but
do
not
prevent
cardiomyocyte
death,
highlighting
need
for
more
effective
therapies
manage
defects
survivors.
This
review
explores
xenobiotic
nature
agents
their
impact
on
health,
aiming
identify
novel
biomarkers
targets
cardiotoxicity.
Research Square (Research Square),
Год журнала:
2025,
Номер
unknown
Опубликована: Апрель 16, 2025
AbstractBackground
The
severe
cardiotoxicity
of
doxorubicin
(Dox)
significantly
restricts
its
clinical
application.
Deubiquitinating
enzymes
(DUBs)
play
pivotal
roles
in
cardiac
pathophysiology
because
their
precise
regulation
protein
function,
localization
and
degradation.Objectives
objective
this
study
was
to
investigate
the
role
molecular
mechanism
ubiquitin-specific
peptidase
20
(USP20),
a
DUB,
doxorubicin-induced
cardiotoxicity.Methods
Cardiomyocyte-specific
USP20-knockout
(USP20-CKO)
mice
were
utilized
assess
USP20
cardiomyopathy
(DIC).
Coimmunoprecipitation
(co-IP)
combined
with
liquid
chromatography‒mass
spectrometry/mass
spectrometry
(LC‒MS/MS)
analysis
employed
screen
substrate
USP20.
Furthermore,
mutant
plasmids
constructed
elucidate
underlying
human
antigen
R
(HuR)
by
Finally,
an
AAV9
vector
used
overexpress
hearts
cardiac-specific
HuR-knockout
interaction
between
HuR.Results
results
revealed
decrease
expression
Dox-stimulated
mouse
cardiomyocytes.
knockout
resulted
increased
cardiomyocyte
ferroptosis
led
DIC.
Mechanistically,
directly
interacted
HuR
through
protease
structural
domain.
Deubiquitination
at
position
154
crucial
for
maintaining
stability
cleaving
K48
ubiquitin
chains
inhibiting
proteasomal
degradation.
Additionally,
bound
GPX4
mRNA
suppress
degradation,
thereby
mitigating
contributing
alleviating
targeted
overexpression
via
cardiomyocytes
alleviated
However,
cardiomyocyte-specific
knockout,
no
longer
had
anti-DIC
effect,
indicating
that
HuR,
as
downstream
target
USP20,
plays
irreplaceable
DIC.Conclusions
Our
findings
indicate
enhances
deubiquitination,
Frontiers in Cardiovascular Medicine,
Год журнала:
2025,
Номер
12
Опубликована: Май 1, 2025
Cardiovascular
diseases
(CVDs)
have
become
the
leading
cause
of
death
globally,
surpassing
infectious
and
other
chronic
illnesses.
The
incidence
mortality
rates
CVDs
are
rising
worldwide,
posing
a
key
challenge
in
public
health.
ubiquitination
system
is
vast
complex.
It
an
important
post-translational
modification
that
plays
crucial
role
various
cellular
processes.
Deubiquitination
catalyzed
by
deubiquitinases
(DUBs),
which
remove
ubiquitin
(Ub)
from
ubiquitinated
proteins,
thereby
reversing
process.
DUBs
play
many
biological
processes,
such
as
DNA
repair,
cell
metabolism,
differentiation,
epigenetic
regulation,
protein
stability
control.
They
also
participate
regulation
signaling
pathways
associated
with
development
progression
CVDs.
In
this
review,
we
primarily
focus
on
pathological
mechanisms
atherosclerosis
(AS),
foam
formation,
vascular
remodeling
(VR),
endothelial-to-mesenchymal
transition
(End-MT),
clonal
hematopoiesis
(CH).
heart,
summarize
involvement
including
heart
failure
(HF),
myocardial
infarction
(MI),
hypertrophy
(MH)
ischemia/reperfusion
(I/R)
injury.
Additionally,
explore
diabetic
cardiomyopathy
(DCM)
use
doxorubicin-induced
cardiotoxicity
clinical
settings.
A
comprehensive
understanding
deubiquitination
may
provide
new
insights
for
treatment
drug
design
Journal of Experimental & Clinical Cancer Research,
Год журнала:
2024,
Номер
43(1)
Опубликована: Авг. 31, 2024
Abstract
Background
Breast
cancer
is
the
most
prevalent
in
women
globally.
Over-activated
estrogen
receptor
(ER)
α
signaling
considered
main
factor
luminal
breast
cancers,
which
can
be
effectively
managed
with
selective
modulators
(SERMs)
like
tamoxifen.
However,
approximately
30–40%
of
ER
+
cases
are
recurrent
after
tamoxifen
therapy.
This
implies
that
treatment
still
hindered
by
resistance
to
Recent
studies
have
suggested
post-translational
modifications
ERα
play
a
significant
role
endocrine
resistance.
The
stability
both
protein
and
its
transcriptome
regulated
balance
between
E3
ubiquitin
ligases
deubiquitinases.
According
current
knowledge,
100
deubiquitinases
encoded
human
genome,
but
it
remains
unclear
critical
Thus,
decoding
key
significantly
impact
signaling,
including
control
expression
stability,
for
improvement
therapeutics.
Methods
We
used
several
positive
cell
lines,
DUB
siRNA
library
screening,
xenograft
models,
endocrine-resistant
(ERα-Y537S)
model
performed
immunoblotting,
real
time
PCR,
RNA
sequencing,
immunofluorescence,
luciferase
activity
assay
investigate
function
USP36
progression
Results
In
this
study,
we
identify
Ubiquitin-specific
peptidase
36
(USP36)
as
deubiquitinase
involved
advancement
screening.
vitro
vivo
showed
USP36,
not
catalytically
inactive
mutant
(C131A),
could
promote
through
signaling.
Conversely,
silencing
inhibited
tumorigenesis.
models
resistant
therapy,
destabilized
form
(Y537S)
restored
sensitivity
Molecular
indicated
K48-linked
polyubiquitination
enhanced
transcriptome.
It
interesting
note
our
results
suggest
novel
biomarker
cancer.
Conclusion
Our
study
revealed
possibility
inhibiting
combined
provide
potential
therapy
