Cell Death and Disease,
Journal Year:
2024,
Volume and Issue:
15(6)
Published: June 12, 2024
Abstract
Full-length
p53
(p53α)
plays
a
pivotal
role
in
maintaining
genomic
integrity
and
preventing
tumor
development.
Over
the
years,
was
found
to
exist
various
isoforms,
which
are
generated
through
alternative
splicing,
initiation
of
translation,
internal
ribosome
entry
site.
either
C-terminally
altered
or
N-terminally
truncated,
exhibit
distinct
biological
roles
compared
p53α,
have
significant
implications
for
development
therapy
resistance.
Due
lack
part
and/or
complete
C-
N-terminal
domains,
ectopic
expression
some
isoforms
failed
induce
canonical
transcriptional
targets
p53α
like
CDKN1A
MDM2
,
even
though
they
may
bind
their
promoters.
Yet,
Δ40p53α
still
activate
subsets
including
BAX
.
Furthermore,
certain
transactivate
novel
p53α.
More
recently,
non-canonical
functions
DNA
repair
different
replication
unrelated
activities
were
discovered,
amplifying
potential
as
master
regulator
physiological
suppressor
human
cells.
Both
regarding
functions,
frequently
exert
dominant
negative
effects
on
its
partners,
is
modified
by
relative
isoform
levels.
Underlying
mechanisms
include
hetero-oligomerization,
changes
subcellular
localization,
aggregation.
These
processes
ultimately
influence
net
give
rise
diverse
cellular
outcomes.
Biological
cancer
Dysregulated
has
been
observed
types
associated
with
clinical
In
conclusion,
expanded
our
understanding
complex
regulatory
network
involving
tumors.
Unraveling
underlying
provides
new
avenues
studies
aiming
at
better
developing
therapeutic
interventions
overcome
Trends in Genetics,
Journal Year:
2021,
Volume and Issue:
37(6), P. 566 - 581
Published: Jan. 20, 2021
Complex
mechanisms
are
in
place
to
maintain
genome
stability.
Ubiquitination
of
chromatin
plays
a
central
role
these
mechanisms.
The
ever-growing
complexity
the
ubiquitin
(Ub)
code
and
modifications
dynamics
challenges
our
ability
fully
understand
how
histone
ubiquitination
regulates
Here
we
review
current
knowledge
on
specific,
low-abundant
events
that
highly
regulated
within
cellular
DNA
damage
response
(DDR),
with
particular
emphasis
latest
discovery
Ub
phosphorylation
as
novel
regulator
DDR
signaling
pathway.
We
discuss
players
involved
potential
implications
(phospho)ubiquitination
structure,
highlight
exciting
open
questions
for
future
research.
Cell Stress,
Journal Year:
2021,
Volume and Issue:
5(6), P. 76 - 85
Published: May 31, 2021
Stress
is
a
central
concept
in
biology
and
has
now
been
widely
used
psychological,
physiological,
social,
even
environmental
fields.
However,
the
of
stress
was
cross-utilized
to
refer
different
elements
system
including
stressful
stimulus,
stressor,
response,
effect.
Here,
we
summarized
evolution
framework
system.
We
find
although
developed
from
Selye's
"general
adaptation
syndrome",
it
expanded
evolved
significantly.
defined
as
state
homeostasis
being
challenged,
both
local
stress.
A
specific
stressor
may
potentially
bring
about
stress,
while
intensity
beyond
threshold
commonly
activate
hypothalamic-pituitary-adrenal
axis
result
systematic
response.
The
indicates
that
includes
three
types:
sustress
(inadequate
stress),
eustress
(good
distress
(bad
stress).
Both
might
impair
normal
physiological
functions
lead
pathological
conditions,
benefit
health
through
hormesis-induced
optimization
homeostasis.
Therefore,
an
optimal
level
essential
for
building
biological
shields
guarantee
life
processes.
Molecular Cell,
Journal Year:
2022,
Volume and Issue:
82(24), P. 4664 - 4680.e9
Published: Nov. 30, 2022
POLQ
is
a
key
effector
of
DSB
repair
by
microhomology-mediated
end-joining
(MMEJ)
and
overexpressed
in
many
cancers.
inhibitors
confer
synthetic
lethality
HR
Shieldin-deficient
cancer
cells,
which
has
been
proposed
to
reflect
critical
dependence
on
the
pathway
MMEJ.
Whether
also
operates
independent
MMEJ
remains
unexplored.
Here,
we
show
that
POLQ-deficient
cells
accumulate
post-replicative
ssDNA
gaps
upon
BRCA1/2
loss
or
PARP
inhibitor
treatment.
Biochemically,
cooperation
between
helicase
polymerase
activities
promotes
RPA
displacement
ssDNA-gap
fill-in,
respectively.
capable
gap
skipping
(MMGS),
generates
deletions
during
resemble
genomic
scars
prevalent
overexpressing
Our
findings
implicate
mutagenic
sealing,
could
drive
genome
evolution
whose
places
dependency
for
protection
cellular
viability.
Science,
Journal Year:
2023,
Volume and Issue:
380(6643), P. 382 - 387
Published: April 27, 2023
Replication
fork
reversal
safeguards
genome
integrity
as
a
replication
stress
response.
DNA
translocases
and
the
RAD51
recombinase
catalyze
reversal.
However,
it
remains
unknown
why
is
required
what
happens
to
machinery
during
We
find
that
uses
its
strand
exchange
activity
circumvent
replicative
helicase,
which
bound
stalled
fork.
not
for
if
helicase
unloaded.
Thus,
we
propose
creates
parental
duplex
behind
used
substrate
by
branch
migration
create
reversed
structure.
Our
data
explain
how
while
maintaining
in
position
poised
restart
synthesis
complete
duplication.
Science Advances,
Journal Year:
2024,
Volume and Issue:
10(3)
Published: Jan. 19, 2024
Mutation
signatures
associated
with
apolipoprotein
B
mRNA
editing
catalytic
polypeptide-like
3A/B
(APOBEC3A/B)
cytidine
deaminases
are
prevalent
across
cancers,
implying
their
roles
as
mutagenic
drivers
during
tumorigenesis
and
tumor
evolution.
APOBEC3A
(A3A)
expression
induces
DNA
replication
stress
increases
the
cellular
dependency
on
ataxia
telangiectasia
Rad3-related
(ATR)
kinase
for
survival.
Nonetheless,
how
A3A
remains
unclear.
We
show
that
without
slowing
forks.
find
single-stranded
(ssDNA)
gaps
through
PrimPol-mediated
repriming.
A3A-induced
ssDNA
repaired
by
multiple
pathways
involving
ATR,
RAD51,
translesion
synthesis.
Both
ATR
inhibition
trapping
of
poly(ADP-ribose)
polymerase
(PARP)
PARP
inhibitor
impair
repair
gaps,
preferentially
killing
A3A-expressing
cells.
When
used
in
combination,
inhibitors
selectively
kill
cells
synergistically
a
manner
dependent
PrimPol-generated
gaps.
Thus,
arises
from
which
confer
therapeutic
vulnerability
to
gap-targeted
inhibitors.
