bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2023,
Volume and Issue:
unknown
Published: Dec. 7, 2023
The
ATM
protein
kinase
is
a
master
regulator
of
the
DNA
damage
response
and
also
an
important
sensor
oxidative
stress.
Analysis
gene
expression
in
Ataxia-telangiectasia
patient
brain
tissue
shows
that
large-scale
transcriptional
changes
occur
cerebellum
correlate
with
level
GC
content
transcribed
genes.
In
human
neuron-like
cells
culture
we
map
locations
poly-ADP-ribose
RNA-DNA
hybrid
accumulation
genome-wide
inhibition
find
these
marks
coincide
high
transcription
levels,
active
histone
marks,
content.
Antioxidant
treatment
reverses
R-loops
regions,
consistent
central
role
ROS
promoting
lesions.
Based
on
results
postulate
transcription-associated
lesions
accumulate
ATM-deficient
single-strand
breaks
PARylation
at
sites
ultimately
generate
compromise
function
lead
to
neurodegeneration
over
time
A-T
patients.
Signal Transduction and Targeted Therapy,
Journal Year:
2025,
Volume and Issue:
10(1)
Published: March 7, 2025
Redox
signaling
acts
as
a
critical
mediator
in
the
dynamic
interactions
between
organisms
and
their
external
environment,
profoundly
influencing
both
onset
progression
of
various
diseases.
Under
physiological
conditions,
oxidative
free
radicals
generated
by
mitochondrial
respiratory
chain,
endoplasmic
reticulum,
NADPH
oxidases
can
be
effectively
neutralized
NRF2-mediated
antioxidant
responses.
These
responses
elevate
synthesis
superoxide
dismutase
(SOD),
catalase,
well
key
molecules
like
nicotinamide
adenine
dinucleotide
phosphate
(NADPH)
glutathione
(GSH),
thereby
maintaining
cellular
redox
homeostasis.
Disruption
this
finely
tuned
equilibrium
is
closely
linked
to
pathogenesis
wide
range
Recent
advances
have
broadened
our
understanding
molecular
mechanisms
underpinning
dysregulation,
highlighting
pivotal
roles
genomic
instability,
epigenetic
modifications,
protein
degradation,
metabolic
reprogramming.
findings
provide
foundation
for
exploring
regulation
mechanistic
basis
improving
therapeutic
strategies.
While
antioxidant-based
therapies
shown
early
promise
conditions
where
stress
plays
primary
pathological
role,
efficacy
diseases
characterized
complex,
multifactorial
etiologies
remains
controversial.
A
deeper,
context-specific
signaling,
particularly
redox-sensitive
proteins,
designing
targeted
aimed
at
re-establishing
balance.
Emerging
small
molecule
inhibitors
that
target
specific
cysteine
residues
proteins
demonstrated
promising
preclinical
outcomes,
setting
stage
forthcoming
clinical
trials.
In
review,
we
summarize
current
intricate
relationship
disease
also
discuss
how
these
insights
leveraged
optimize
strategies
practice.
Redox Biology,
Journal Year:
2024,
Volume and Issue:
75, P. 103269 - 103269
Published: July 16, 2024
The
ataxia
telangiectasia
mutated
(ATM)
protein
kinase
is
best
known
as
a
master
regulator
of
the
DNA
damage
response.
However,
accumulating
evidence
has
unveiled
an
equally
vital
function
for
ATM
in
sensing
oxidative
stress
and
orchestrating
cellular
antioxidant
defenses
to
maintain
redox
homeostasis.
can
be
activated
through
non-canonical
pathway
involving
intermolecular
disulfide
crosslinking
dimers,
distinct
from
its
canonical
activation
by
double-strand
breaks.
Structural
studies
have
elucidated
conformational
changes
that
allow
switch
into
active
redox-sensing
state
upon
oxidation.
Notably,
loss
results
elevated
reactive
oxygen
species
(ROS)
levels,
altered
profiles,
mitochondrial
dysfunction
across
multiple
cell
types
tissues.
This
arising
deficiency
been
implicated
central
driver
neurodegenerative
phenotypes
ataxia-telangiectasia
(A-T)
patients,
potentially
mechanisms
damage,
PARP
hyperactivation,
widespread
aggregation.
Moreover,
defective
oxidation
disrupts
transcriptional
programs
RNA
metabolism,
with
detrimental
impacts
on
neuronal
Significantly,
therapy
ameliorate
organismal
abnormalities
various
ATM-deficient
models.
review
synthesizes
recent
advances
illuminating
multifaceted
roles
preserving
balance
mitigating
insults,
providing
unifying
paradigm
understanding
complex
pathogenesis
A-T
disease.
Biochemistry,
Journal Year:
2024,
Volume and Issue:
63(7), P. 827 - 842
Published: March 14, 2024
Telomeres
are
specialized
structures,
found
at
the
ends
of
linear
chromosomes
in
eukaryotic
cells,
that
play
a
crucial
role
maintaining
stability
and
integrity
genomes.
They
composed
repetitive
DNA
sequences,
ssDNA
overhangs,
several
associated
proteins.
The
length
telomeres
is
linked
to
cellular
aging
humans,
deficiencies
their
maintenance
with
various
diseases.
Key
structural
motifs
serve
protect
vulnerable
chromosomal
ends.
Telomeric
also
has
ability
form
diverse
complex
higher-order
including
T-loops,
D-loops,
R-loops,
G-loops,
G-quadruplexes,
i-motifs,
complementary
C-rich
strand.
While
many
essential
proteins
have
been
identified,
intricacies
interactions
details
still
not
fully
understood.
This
Perspective
highlights
recent
advancements
comprehending
structures
human
telomeres.
It
emphasizes
significance
telomeres,
explores
telomeric
motifs,
delves
into
biology
surrounding
telomerase.
Furthermore,
loops,
topologies,
contribute
safeguarding
discussed.
Cell Reports,
Journal Year:
2024,
Volume and Issue:
43(3), P. 113896 - 113896
Published: March 1, 2024
The
ataxia
telangiectasia
mutated
(ATM)
protein
kinase
is
a
master
regulator
of
the
DNA
damage
response
and
also
an
important
sensor
oxidative
stress.
Analysis
gene
expression
in
ataxia-telangiectasia
(A-T)
patient
brain
tissue
shows
that
large-scale
transcriptional
changes
occur
cerebellum
correlate
with
level
guanine-cytosine
(GC)
content
transcribed
genes.
In
human
neuron-like
cells
culture,
we
map
locations
poly(ADP-ribose)
RNA-DNA
hybrid
accumulation
genome-wide
ATM
inhibition
find
these
marks
coincide
high
transcription
levels,
active
histone
marks,
GC
content.
Antioxidant
treatment
reverses
R-loops
regions,
consistent
central
role
reactive
oxygen
species
promoting
lesions.
Based
on
results,
postulate
transcription-associated
lesions
accumulate
ATM-deficient
single-strand
breaks
PARylation
at
sites
ultimately
generate
compromise
function
lead
to
neurodegeneration
over
time
A-T
patients.
Biomedicines,
Journal Year:
2024,
Volume and Issue:
12(5), P. 1074 - 1074
Published: May 13, 2024
Parkinson’s
disease
(PD),
a
progressive
neurodegenerative
disease,
has
no
cure,
and
current
therapies
are
not
effective
at
halting
progression.
The
affects
mid-brain
dopaminergic
neurons
and,
subsequently,
the
spinal
cord,
contributing
to
many
debilitating
symptoms
associated
with
PD.
GTP-binding
protein,
Rho,
plays
significant
role
in
cellular
pathology
of
downstream
effector
Rho-associated
kinase
(ROCK),
multiple
functions,
including
microglial
activation
induction
inflammatory
responses.
Activated
microglia
have
been
implicated
diseases,
PD,
that
initiate
responses,
leading
neuron
death.
Calpain
expression
activity
is
increased
following
glial
activation,
which
triggers
Rho-ROCK
pathway
induces
T
cell
migration
as
well
mediates
toxic
α-synuclein
(α-syn)
aggregation
death,
indicating
pivotal
for
calpain
degenerative
processes
Increased
may
represent
new
mechanism
oxidative
damage
aging.
This
review
will
summarize
stress
α-syn
aggregation,
their
influence
on
process
PD
aging,
possible
strategies
research
directions
therapeutic
intervention.
Molecular Medicine,
Journal Year:
2025,
Volume and Issue:
31(1)
Published: Feb. 20, 2025
Ionizing
radiation
causes
three
divergent
effects
in
the
human
body:
On
one
side,
tissue
death
(=
deterministic
effects)
sets
on,
on
other
mutations
and
cancer
growth
stochastic
can
occur.
In
recent
years,
additional
phenomenon
of
accelerated
aging
has
come
to
light.
following,
we
argue
that
these
seemingly
contradictory
responses
namely:
(i)
increased
growth,
(ii)
ablation
or
(iii)
senescence,
share
an
underlying
cause
from
damage
at
lamin
A
C-terminus.
words,
besides
typically
described
genomic
impact,
propose
destabilization
pathway
via
oxidation
nuclear
envelope.
We
five
concrete
hypotheses
draw
a
direct
mechanistic
model
cellular
oxidative
stress,
micronuclei
clinical
symptoms.
conjunction
with
B
compensation,
might
be
able
explain
why
dominate.
If
our
holds
true,
novel
target
for
radiotherapeutics
radiooncology
arises,
rationale
closer
connect
laminopathy
radioprotection
research.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: June 26, 2024
Programmed
telomere
shortening
limits
tumorigenesis
through
the
induction
of
replicative
senescence.
Here
we
address
three
long-standing
questions
concerning
First,
show
that
ATM
kinase
is
solely
responsible
for
Senescence
was
delayed
by
inhibition
(ATMi)
or
overexpression
TRF2,
shelterin
subunit
dedicated
to
repression.
In
contrast,
there
no
evidence
ATR
signaling
contributing
senescence
even
when
ATMi
combined
with
inhibition.
Second,
can
induce
apparently
normal
cell
divisions
in
a
subset
senescent
cells,
indicating
be
reversed.
Third,
extended
life
span
at
low
(physiological)
oxygen
due
diminished
activity.
At
oxygen,
cells
decreased
response
dysfunctional
telomeres
and
genome-wide
DSBs
compared
20%
oxygen.
As
this
effect
could
reversed
NAC,
attenuated
critically
short
resulting
likely
ROS-induced
formation
cysteine
disulfide-bridges
crosslink
dimers
into
form
not
activated
DSBs.
These
findings
how
primary
human
detect
shortened
reveal
molecular
mechanism
underlying
tumor
suppressor
pathway.