International Journal of Molecular Sciences,
Год журнала:
2020,
Номер
21(21), С. 8273 - 8273
Опубликована: Ноя. 4, 2020
Steroid
hormone
signaling
induces
vast
gene
expression
programs
which
necessitate
the
local
formation
of
transcription
factories
at
regulatory
regions
and
large-scale
alterations
genome
architecture
to
allow
communication
among
distantly
related
cis-acting
regions.
This
involves
major
stress
genomic
DNA
level.
Transcriptionally
active
are
generally
instable
prone
breakage
due
torsional
depletion
nucleosomes
that
make
more
accessible
damaging
agents.
A
dedicated
damage
response
(DDR)
is
therefore
essential
maintain
integrity
these
exposed
The
DDR
a
complex
network
involving
sensor
proteins,
such
as
poly(ADP-ribose)
polymerase
1
(PARP-1),
DNA-dependent
protein
kinase
catalytic
subunit
(DNA-PKcs),
ataxia–telangiectasia-mutated
(ATM)
ATM
Rad3-related
(ATR)
kinase,
central
regulators.
tight
interplay
between
steroid
receptors
has
been
unraveled
recently.
Several
repair
factors
interact
with
androgen
estrogen
support
their
transcriptional
functions.
Conversely,
both
directly
control
agents
involved
in
DDR.
Impaired
also
exploited
by
tumors
acquire
advantageous
mutations.
Cancer
cells
often
harbor
germline
or
somatic
genes,
association
disease
outcome
treatment
led
intensive
efforts
towards
identifying
selective
inhibitors
targeting
players
this
process.
PARP-1
now
approved
for
ovarian,
breast,
prostate
cancer
specific
alterations.
Additional
DDR-targeting
being
evaluated
clinical
studies
either
single
combination
treatments
eliciting
(e.g.,
radiation
therapy,
including
targeted
radiotherapy,
chemotherapy)
addressing
targets
maintenance
integrity.
Recent
preclinical
findings
made
dysfunction
hormone-dependent
-independent
breast
presented.
Importantly,
anti-hormonal
therapy
inhibition
potential
enhance
efficacy
but
still
needs
further
investigation.
Cancers,
Год журнала:
2019,
Номер
11(1), С. 119 - 119
Опубликована: Янв. 20, 2019
Epithelial
ovarian
cancer
(EOC)
is
the
most
lethal
gynecological
cancer.
It
initially
responsive
to
cisplatin
and
carboplatin,
two
DNA
damaging
agents
used
in
first
line
therapy.
However,
almost
invariably,
patients
relapse
with
a
tumor
resistant
subsequent
treatment
platinum
containing
drugs.
Several
mechanisms
associated
development
of
acquired
drug
resistance
have
been
reported.
Here
we
focused
our
attention
on
repair
mechanisms,
which
are
fundamental
for
recognition
removal
adducts
hence
ability
these
drugs
exert
their
activity.
We
analyzed
major
pathways
potentially
involved
resistance,
detailing
gene
mutation,
duplication
or
deletion
as
well
polymorphisms
potential
biomarkers
development.
dissected
ways
overcome
repair-associated
thanks
new
combinations
and/or
directly
targeting
proteins
taking
advantage
vulnerability
arising
from
defects
EOCs.
Journal of Biological Chemistry,
Год журнала:
2020,
Номер
295(13), С. 4134 - 4170
Опубликована: Фев. 15, 2020
Expansions
of
simple
tandem
repeats
are
responsible
for
almost
50
human
diseases,
the
majority
which
severe,
degenerative,
and
not
currently
treatable
or
preventable.
In
this
review,
we
first
describe
molecular
mechanisms
repeat-induced
toxicity,
is
connecting
link
between
repeat
expansions
pathology.
We
then
survey
alternative
DNA
structures
that
formed
by
expandable
review
evidence
formation
these
at
core
instability.
Next,
consequences
presence
long
structure-forming
level:
somatic
intergenerational
instability,
fragility,
mutagenesis.
discuss
reasons
gender
bias
in
instability
tissue
specificity
also
known
pathways
replication,
transcription,
repair,
chromatin
state
interact
thereby
promote
possible
persistence
disease-causing
genome.
suggesting
a
payoff
advantages
having
abundant
simple-sequence
eukaryotic
genome
function
evolvability.
Finally,
two
unresolved
fundamental
questions:
(i)
why
does
behavior
differ
model
systems
pedigrees,
(ii)
can
use
current
knowledge
on
to
cure
expansion
diseases?
Frontiers in Oncology,
Год журнала:
2020,
Номер
10
Опубликована: Фев. 20, 2020
Cancer
stem
cells
(CSC)
are
a
distinct
subpopulation
within
tumor.
They
able
to
self-renew
and
differentiate
possess
high
capability
repair
DNA
damage,
exhibit
low
levels
of
reactive
oxygen
species
(ROS),
proliferate
slowly.
These
features
render
CSC
resistant
various
therapies,
including
radiation
therapy
(RT).
Eradication
as
many
possible
is
requirement
for
an
effective
antineoplastic
treatment
therefore
utmost
importance
the
patient.
This
makes
prime
targets
any
therapeutic
approach.
Albeit
clinical
data
still
scarce,
experimental
first
trials
give
hope
that
CSC-based
has
potential
improve
treatment,
especially
tumors
known
be
resistant,
such
glioblastoma.
In
this
review,
we
will
discuss
in
context
RT,
describe
mechanisms
resistance,
examine
possibilities
biomarkers,
new
approaches.
Annual Review of Genetics,
Год журнала:
2020,
Номер
54(1), С. 25 - 46
Опубликована: Июль 14, 2020
Accurate
DNA
repair
and
replication
are
critical
for
genomic
stability
cancer
prevention.
RAD51
its
gene
family
key
regulators
of
fidelity
through
diverse
roles
in
double-strand
break
repair,
stress,
meiosis.
is
an
ATPase
that
forms
a
nucleoprotein
filament
on
single-stranded
DNA.
has
the
function
finding
invading
homologous
sequences
to
enable
accurate
timely
repair.
Its
paralogs,
which
arose
from
ancient
duplications
RAD51,
have
evolved
regulate
promote
function.
Underscoring
importance,
misregulation
associated
with
diseases
such
as
Fanconi
anemia.
In
this
review,
we
focus
mammalian
structure
highlight
use
model
systems
mechanistic
understanding
cellular
roles.
We
also
discuss
how
members
contributes
disease
consider
new
approaches
pharmacologically
inhibit
RAD51.
Cells
manage
to
survive,
thrive,
and
divide
with
high
accuracy
despite
the
constant
threat
of
DNA
damage.
have
evolved
several
systems
that
efficiently
repair
spontaneous,
isolated
lesions
a
degree
accuracy.
Ionizing
radiation
few
radiomimetic
chemicals
can
produce
clustered
damage
comprising
complex
arrangements
single-strand
double-strand
breaks
(DSBs).
There
is
substantial
evidence
more
mutagenic
cytotoxic
than
Radiation-induced
has
proven
difficult
study
because
spectrum
induced
very
complex,
are
randomly
distributed
throughout
genome.
Nonetheless,
it
fairly
well-established
radiation-induced
damage,
including
non-DSB
DSB
lesions,
poorly
repaired
or
fail
repair,
accounting
for
greater
effects
compared
lesions.
High
linear
energy
transfer
(LET)
charged
particle
per
unit
dose
low
LET
produces
Studies
I-SceI
nuclease
demonstrate
nuclease-induced
clusters
also
cytotoxic,
indicating
this
cytotoxicity
independent
radiogenic
chemically
“dirty”
ends.
The
poor
DSBs
at
least
in
part
reflects
inhibition
canonical
NHEJ
by
short
fragments.
This
shifts
toward
HR
perhaps
alternative
NHEJ,
result
chromothripsis-mediated
genome
instability
cell
death.
These
principals
important
cancer
treatment
radiation.
