Trends in Genetics,
Journal Year:
2024,
Volume and Issue:
40(9), P. 757 - 771
Published: May 23, 2024
The
tumour-suppressive
roles
of
BRCA1
and
2
have
been
attributed
to
three
seemingly
distinct
functions
-
homologous
recombination,
replication
fork
protection,
single-stranded
(ss)DNA
gap
suppression
their
relative
importance
is
under
debate.
In
this
review,
we
examine
the
origin
resolution
ssDNA
gaps
discuss
recent
advances
in
understanding
role
BRCA1/2
suppression.
There
are
ample
data
showing
that
accumulation
BRCA1/2-deficient
cells
linked
genomic
instability
chemosensitivity.
However,
it
remains
unclear
whether
there
a
causative
function
cannot
unambiguously
be
dissected
from
other
functions.
We
therefore
conclude
closely
intertwined
not
mutually
exclusive.
DNA repair,
Journal Year:
2024,
Volume and Issue:
144, P. 103775 - 103775
Published: Oct. 19, 2024
The
mechanisms
by
which
poly(ADP-ribose)
polymerase
1
(PARP1)
inhibitors
(PARPi)s
inflict
replication
stress
and/or
DNA
damage
are
potentially
numerous.
PARPi
toxicity
could
derive
from
loss
of
its
catalytic
activity
physical
trapping
PARP1
onto
that
perturbs
not
only
function
in
repair
and
replication,
but
also
obstructs
compensating
pathways.
combined
disruption
with
either
the
hereditary
breast
ovarian
cancer
genes,
BRCA1
or
BRCA2
(BRCA),
results
synthetic
lethality.
This
has
driven
development
PARP
as
therapies
for
BRCA-mutant
cancers.
In
this
review,
we
focus
on
recent
findings
highlight
activity,
rather
than
PARPi-induced
allosteric
trapping,
central
to
efficacy
BRCA
deficient
cells.
However,
review
PARP-trapping
is
an
effective
strategy
other
genetic
deficiencies.
Together,
conclude
mechanism-of-action
unilateral;
enhanced
differentially
killing
depending
context.
Therefore,
effectively
targeting
cells
requires
intricate
understanding
their
key
underlying
vulnerabilities.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2025,
Volume and Issue:
unknown
Published: Jan. 8, 2025
The
human
genome
contains
numerous
repetitive
nucleotide
sequences
that
display
a
propensity
to
fold
into
non-canonical
DNA
structures
including
G-quadruplexes
(G4s).
G4s
have
both
positive
and
negative
impacts
on
various
aspects
of
nucleic
acid
metabolism
replication,
repair
RNA
transcription.
Poly
(ADP-ribose)
polymerase
(PARP1),
an
important
anticancer
drug
target,
has
been
recently
shown
bind
subset
G4s,
undergo
auto-PARylation.
mechanism
this
interaction,
however,
is
poorly
understood.
Utilizing
Mass
Photometry
(MP)
single-molecule
total
internal
reflection
fluorescence
microscopy
(smTIRFM),
we
demonstrate
PARP1
dynamically
interacts
with
1:1
stoichiometry.
Interaction
single
molecule
nicked
or
containing
G4
primer-template
junction
sufficient
activate
robust
auto-PARylation
resulting
in
the
addition
poly
chains
molecular
weight
several
hundred
kDa.
Pharmacological
PARP
inhibitors
EB-47,
Olaparib
Veliparib
differently
affect
retention
G4-containing
compared
DNA.
Nature Communications,
Journal Year:
2025,
Volume and Issue:
16(1)
Published: Jan. 25, 2025
To
tolerate
oxidative
stress,
cells
enable
DNA
repair
responses
often
sensitive
to
poly(ADP-ribose)
(PAR)
polymerase
1
and
2
(PARP1/2)
inhibition—an
intervention
effective
against
cancers
lacking
BRCA1/2.
Here,
we
demonstrate
that
mutating
the
CHD6
chromatin
remodeler
sensitizes
PARP1/2
inhibitors
in
a
manner
distinct
from
BRCA1,
recruitment
damage
requires
cooperation
between
PAR-
DNA-binding
domains
essential
for
nucleosome
sliding
activity.
displays
direct
PAR-binding,
interacts
with
PARP-1
other
PAR-associated
proteins,
combined
DNA-
PAR-binding
loss
eliminates
relocalization
damage.
While
does
not
impair
RAD51
foci
formation
or
double-strand
break
repair,
it
causes
sensitivity
replication
PARP1/2-trapping
Pol
ζ
inhibitor-induced
γH2AX
accumulation
S-phase.
pathway
screening
reveals
elicits
insufficiency
apurinic-apyrimidinic
endonuclease
(APEX1)
activity
genomic
abasic
site
accumulation.
We
reveal
APEX1-linked
roles
important
understanding
inhibitor
sensitivity.
Discovering
molecular
pathways
sensitize
(PARP)-
trapping
is
anti-cancer
therapy.
authors
report
inactivation
of
remodelling
enzyme
PARP
via
reduced
on
chromatin,
stress.
Chinese Medical Journal,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Feb. 11, 2025
Abstract
Poly(ADP-ribose)
polymerase
(PARP)
inhibitors
(PARPis)
have
emerged
as
critical
agents
for
cancer
therapy.
By
inhibiting
the
catalytic
activity
of
PARP
enzymes
and
trapping
them
in
DNA,
PARPis
disrupt
DNA
repair,
ultimately
leading
to
cell
death,
particularly
cells
with
homologous
recombination
repair
deficiencies,
such
those
harboring
BRCA
mutations.
This
review
delves
into
mechanisms
action
anticancer
treatments,
including
inhibition
synthetic
lethality,
replication
stress.
Furthermore,
clinical
applications
various
cancers
their
adverse
effects
well
combinations
other
therapies
underlying
resistance
are
summarized.
provides
comprehensive
insights
role
a
particular
focus
on
potential
PARPi-based
precision
medicine
treatment.
DNA,
Journal Year:
2025,
Volume and Issue:
5(2), P. 17 - 17
Published: April 1, 2025
Cancers
that
arise
from
germline
mutations
of
breast
cancer
associated
gene
1
(BRCA1),
which
is
a
crucial
player
in
homologous
recombination
(HR)
DNA
repair,
are
vulnerable
to
DNA-damaging
agents
such
as
platinum
and
PARP
inhibitors
(PARPis).
Increasing
evidence
suggests
BRCA1
an
essential
driver
all
phases
the
cell
cycle,
thereby
maintaining
orderly
steps
during
cycle
progression.
Specifically,
loss
activity
causes
S-phase,
G2/M,
spindle
checkpoints,
centrosome
duplication
be
dysregulated,
blocking
proliferation
inducing
apoptosis.
In
vertebrates,
HR
genes
and/or
BRCA2
lethal,
since
prerequisite
for
genome
integrity.
Thus,
cells
utilize
alternative
repair
pathways
non-homologous
end
joining
(NHEJ)
cope
with
function.
this
review,
we
attempt
update
discuss
how
these
novel
components
regulating
damage
(DDR)
BRCA1-deficient
cancers.
Frontiers in Cell and Developmental Biology,
Journal Year:
2024,
Volume and Issue:
12
Published: July 1, 2024
Temozolomide
(TMZ)
is
a
methylating
agent
used
as
the
first-line
drug
in
chemotherapy
of
glioblastomas.
However,
cancer
cells
eventually
acquire
resistance,
necessitating
development
TMZ-potentiating
therapy
agents.
TMZ
induces
several
DNA
base
adducts,
including
