DNA repair,
Год журнала:
2024,
Номер
145, С. 103786 - 103786
Опубликована: Ноя. 14, 2024
In
recent
years,
numerous
reports
indicated
that,
besides
pathogen
infections,
DNA
replication
stress
and
defective
repair
can
trigger
the
innate
immune
response
by
introducing
a
state
of
viral
mimicry,
due
to
cytosolic
accumulation
self-nucleic
acid
species,
which
culminates
in
activation
type
I
interferon
(IFN)
pathway.
turn,
IFN
upregulates
variety
factors
mutually
implicated
immune-
genome-related
mechanisms,
shedding
light
on
unprecedented
causality
between
genome
stability
immunity.
Intriguingly,
addition
being
induced
stress,
IFN-regulated
also
promote
it,
pinpointing
signaling
as
both
consequence
cause
stress.
Here,
we
provide
an
overview
molecular
mechanisms
evolutionary
conserved
crosstalk
maintenance
immunity,
highlighting
role
IFN-stimulated
gene
15
(ISG15),
appears
be
at
hub
this
intersection.
Moreover,
discuss
potential
significance
clinical
implications
immune-mediated
modulation
upon
infection
human
diseases
such
cancer
autoinflammatory
syndromes.
Finally,
relevant
open
questions
future
directions.
Journal of Clinical Investigation,
Год журнала:
2024,
Номер
134(14)
Опубликована: Июль 14, 2024
Mutations
in
the
tumor-suppressor
genes
BRCA1
and
BRCA2
resulting
BRCA1/2
deficiency
are
frequently
identified
breast,
ovarian,
prostate,
pancreatic,
other
cancers.
Poly(ADP-ribose)
polymerase
(PARP)
inhibitors
(PARPis)
selectively
kill
BRCA1/2-deficient
cancer
cells
by
inducing
synthetic
lethality,
providing
an
effective
biomarker-guided
strategy
for
targeted
therapy.
However,
a
substantial
fraction
of
patients
carrying
mutations
do
not
respond
to
PARPis,
most
develop
resistance
PARPis
over
time,
highlighting
major
obstacle
PARPi
therapy
clinic.
Recent
studies
have
revealed
that
changes
specific
functional
defects
cells,
particularly
their
suppressing
protecting
single-stranded
DNA
gaps,
contribute
gain
or
loss
PARPi-induced
lethality.
These
findings
only
shed
light
on
mechanism
action
but
also
lead
revised
models
explain
how
BRCA-deficient
cells.
Furthermore,
new
mechanistic
principles
sensitivity
emerged
from
these
studies,
generating
potentially
useful
guidelines
predicting
response
design
therapies
overcoming
resistance.
In
this
Review,
we
will
discuss
recent
put
them
context
with
classic
views
aiming
stimulate
development
therapeutic
strategies
overcome
improve
Proceedings of the National Academy of Sciences,
Год журнала:
2025,
Номер
122(2)
Опубликована: Янв. 7, 2025
CAG/CTG
repeats
are
prone
to
expansion,
causing
several
inherited
human
diseases.
The
initiating
sources
of
DNA
damage
which
lead
inaccurate
repair
the
repeat
tract
cause
expansions
not
fully
understood.
Expansion-prone
actively
transcribed
and
forming
stable
R-loops
with
hairpin
structures
on
displaced
single-stranded
(S-loops).
We
previously
determined
that
by
Saccharomyces
cerevisiae
cytosine
deaminase,
Fcy1,
was
required
for
both
fragility
instability
tracts
engaged
in
R-loops.
To
determine
whether
this
mechanism
is
more
universal,
we
expressed
cytidine
deaminases
APOBEC3A
(A3A),
APOBEC3B
(A3B),
or
activation-induced
deaminase
(AID)
our
yeast
system.
show
mutagenic
activity
Apolipoprotein
B
messenger
RNA-editing
enzyme,
catalytic
polypeptides
causes
instability,
A3A
having
greatest
effect
followed
A3B
least
from
AID.
A3A-induced
exacerbated
enrichment
at
site.
A3B-induced
dependent
MutLγ
nuclease
a
lesser
extent,
base
excision
factors.
Deaminase
assays
substrates
containing
CTG
GTC
triplet
sequences
revealed
prefers
cytidines
within
loop,
bulges
stem
alter
preferred
locations.
Analysis
RNA
expression
levels
cortex
samples
brain
tissue
exhibits
its
elevated
Huntington’s
disease
(HD)
patient
samples.
These
results
implicate
deamination
as
potential
source
HD
other
expansion
disorders.
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Июль 27, 2024
Clinical
success
with
poly
(ADP-ribose)
polymerase
inhibitors
(PARPi)
is
impeded
by
inevitable
resistance
and
associated
cytotoxicity.
Depletion
of
Amplified
in
Liver
Cancer
1
(ALC1),
a
chromatin-remodeling
enzyme,
can
overcome
these
limitations
hypersensitizing
BReast
CAncer
genes
1/2
(BRCA1/2)
mutant
cells
to
PARPi.
Here,
we
demonstrate
that
PARPi
hypersensitivity
upon
ALC1
loss
reliant
on
its
role
promoting
the
repair
chromatin
buried
abasic
sites.
We
show
enhances
ability
site
processing
Apurinic/Apyrimidinic
endonuclease
(APE1)
cleave
nucleosome-occluded
However,
unrepaired
sites
ALC1-deficient
are
readily
accessed
APE1
at
nucleosome-free
replication
forks.
cleavage
leads
fork
breakage
trapping
PARP1/2
treatment,
resulting
hypersensitivity.
Collectively,
our
studies
reveal
how
barrier
lesions
uncover
as
mechanism
Loss
(ALC1)
has
been
shown
confer
PARP
inhibitor
BRCA-mutant
cells.
authors
cells,
cleaves
forks
DNA
breaks
thereby
sensitivity.
The EMBO Journal,
Год журнала:
2024,
Номер
43(15), С. 3240 - 3255
Опубликована: Июнь 17, 2024
Abstract
Mutational
patterns
caused
by
APOBEC3
cytidine
deaminase
activity
are
evident
throughout
human
cancer
genomes.
In
particular,
the
APOBEC3A
family
member
is
a
potent
genotoxin
that
causes
substantial
DNA
damage
in
experimental
systems
and
tumors.
However,
mechanisms
ensure
genome
stability
cells
with
active
unknown.
Through
an
unbiased
genome-wide
screen,
we
define
Structural
Maintenance
of
Chromosomes
5/6
(SMC5/6)
complex
as
essential
for
cell
viability
when
active.
We
observe
absence
mutagenesis
tumors
SMC5/6
dysfunction,
consistent
synthetic
lethality.
Cancer
depleted
incur
from
during
replication.
Further,
results
replication
tract
lengthening
which
dependent
on
PrimPol,
re-initiation
synthesis
downstream
APOBEC3A-induced
lesions.
Loss
abrogates
elongated
tracts
increases
breaks
upon
activity.
Our
findings
indicate
fork
reflects
response
to
promotes
SMC5/6-dependent
manner.
Therefore,
presents
potential
therapeutic
vulnerability
APOBEC3A.
Ataxia
telangiectasia
and
Rad3-related
(ATR)
inhibition
triggers
a
surge
in
origin
firing,
resulting
increased
levels
of
single-stranded
DNA
(ssDNA)
that
rapidly
deplete
all
available
RPA.
This
leaves
ssDNA
unprotected
susceptible
to
breakage,
phenomenon
known
as
replication
catastrophe.
However,
the
mechanism
by
which
breaks
remains
unclear.
Here,
we
reveal
APOBEC3B
is
key
enzyme
targeting
at
forks,
initiating
reaction
cascade
induces
fork
collapse
poly(ADP-ribose)
polymerase
1
(PARP1)
hyperactivation.
Mechanistically,
demonstrate
uracils
generated
forks
are
removed
UNG2,
abasic
sites
subsequently
cleaved
APE1
endonuclease.
Moreover,
show
APE1-mediated
cleavage
critical
enzymatic
step
for
PARP1
hyperactivation
cells,
regardless
how
on
DNA.
Last,
APOBEC3B-induced
trapping
double-strand
drive
cell
sensitivity
ATR
inhibition,
creating
context
synthetic
lethality
when
coupled
with
PARP
inhibitors.
Cell Reports,
Год журнала:
2024,
Номер
43(5), С. 114205 - 114205
Опубликована: Май 1, 2024
The
advent
of
PARP
inhibitors
(PARPis)
has
profoundly
changed
the
treatment
landscape
BRCA1/BRCA2-mutated
cancers.
Despite
this,
development
resistance
to
these
compounds
become
a
major
challenge.
Hence,
detailed
understanding
mechanisms
underlying
PARPi
sensitivity
is
crucially
needed.
Here,
we
show
that
loss
POLE3-POLE4
subunits
DNA
polymerase
epsilon
(Polε)
strongly
sensitizes
cancer
cells
PARPis
in
Polε
level-independent
manner.
Loss
not
associated
with
defective
RAD51
foci
formation,
excluding
defect
homologous
recombination.
On
contrary,
triggers
replicative
gap
accumulation
knockout
(KO)
PRIMPOL-dependent
In
addition
further
BRCA1-silenced
PARPis.
Importantly,
knockdown
53BP1
does
rescue
KO
cells,
bypassing
common
mechanism
and
outlining
potential
strategy
sensitize
