G-quadruplex stabilization provokes DNA breaks in human PKD1, revealing a second hit mechanism for ADPKD
Nature Communications,
Год журнала:
2025,
Номер
16(1)
Опубликована: Янв. 2, 2025
Abstract
The
“secondhit”
pathway
is
responsible
for
biallelic
inactivation
of
many
tumor
suppressors,
where
a
pathogenic
germline
allele
joined
by
somatic
mutation
the
remaining
functional
allele.
mechanisms
are
unresolved,
but
human
PKD1
suppressor
good
experimental
model
identifying
molecular
determinants.
Inactivation
results
in
autosomal
dominant
polycystic
kidney
disease,
very
common
disorder
characterized
accumulation
fluid-filled
cysts
and
end-stage
renal
disease.
Since
follows
second
hit
mouse
Pkd1
heterozygotes
do
not,
we
reasoned
that
there
likely
difference
explains
elevated
mutagenesis
gene.
Here
demonstrate
guanine
quadruplex
DNA
structures
abundant
throughout
human,
not
mouse,
they
activate
damage
response.
Our
suggest
DNAs
provoke
breaks
,
providing
potential
mechanism
cystogenesis
disease
specifically
quadruplex-rich
suppressors
generally.
Язык: Английский
Impact of imidazolium-based ionic liquid, functionalized with aromatic compounds, on thermophysical and aggregation properties
Journal of Molecular Liquids,
Год журнала:
2025,
Номер
unknown, С. 127579 - 127579
Опубликована: Апрель 1, 2025
Язык: Английский
Translating G-quadruplex ligands from bench to bedside: a Stephen Neidle’s legacy
Medicinal Chemistry Research,
Год журнала:
2024,
Номер
unknown
Опубликована: Сен. 7, 2024
Язык: Английский
A CD Study of a Structure-Based Selection of N-Heterocyclic Bis-Carbene Gold(I) Complexes as Potential Ligands of the G-Quadruplex-Forming Human Telomeric hTel23 Sequence
Molecules,
Год журнала:
2024,
Номер
29(22), С. 5446 - 5446
Опубликована: Ноя. 19, 2024
Herein,
we
report
the
structure-based
selection
via
molecular
docking
of
four
N-heterocyclic
bis-carbene
gold(I)
complexes,
whose
potential
as
ligands
for
hTel23
G-quadruplex
structure
has
been
investigated
using
circular
dichroism
(CD)
spectroscopy,
CD
melting,
and
polyacrylamide
gel
electrophoresis
(PAGE).
The
complex
containing
a
bis(1,2,3,4,6,7,8,9-octahydro-11H-11λ3-pyridazino[1,2-a]indazol-11-yl)
scaffold
induces
transition
from
hybrid
(3
+
1)
topology
to
prevalent
parallel
conformation,
whereas
featuring
bis(2-(2-acetamidoethyl)-3λ3-imidazo[1,5-a]pyridin-3(2H)-yl)
moiety
disrupted
original
structure.
These
results
deserve
particular
attention
in
light
recent
findings
on
pathological
involvements
G-quadruplexes
neurodegenerative
diseases.
Язык: Английский
G-quadruplexes in long non-coding RNAs and their interactions with proteins
International Journal of Biological Macromolecules,
Год журнала:
2024,
Номер
278, С. 134946 - 134946
Опубликована: Авг. 24, 2024
Язык: Английский
A Novel G-Quadruplex Structure within Apolipoprotein E Promoter: A New Promising Target in Cancer and Dementia Fight?
ACS Omega,
Год журнала:
2024,
Номер
9(45), С. 45203 - 45213
Опубликована: Окт. 30, 2024
Human
apolipoprotein
E
(APOE)
is
a
crucial
lipid
transport
glycoprotein
involved
in
various
biological
processes,
including
metabolism,
immune
response,
and
neurodegeneration.
Elevated
APOE
levels
are
linked
to
poor
prognosis
several
cancers
increased
risk
of
Alzheimer's
disease
(AD).
Therefore,
modulating
expression
presents
promising
therapeutic
strategy
for
both
cancer
AD.
Considering
the
pivotal
role
G-quadruplex
(G4)
structures
medicinal
chemistry
as
modulators
gene
expression,
here,
we
present
newly
discovered
structure
within
ApoE
promoter.
Bioinformatic
analysis
identified
21
potential
G4-forming
sequences
promoter,
with
more
proximal
transcription
start
site,
pApoE,
showing
highest
G-score.
Biophysical
studies
confirmed
folding
pApoE
into
stable
parallel
G4
under
physiological
conditions,
supported
by
circular
dichroism,
NMR
spectroscopy,
UV-melting,
quantitative
PCR
stop
assay.
Moreover,
ability
modulate
pApoE-G4
was
demonstrated
using
G4-stabilizing
ligands
(HPHAM,
Braco19,
PDS),
which
thermal
stability
pApoE-G4.
In
contrast,
peptide
nucleic
acid
conjugates
were
synthesized
disrupt
formation,
effectively
hybridizing
sequences,
confirming
unfold
structures.
Overall,
our
findings
provide
mainstay
future
approaches
targeting
ApoE-G4s
regulate
offering
advancements
AD
treatment.
Язык: Английский
Myriad factors and pathways influencing tumor radiotherapy resistance
Open Life Sciences,
Год журнала:
2024,
Номер
19(1)
Опубликована: Янв. 1, 2024
Abstract
Radiotherapy
is
a
cornerstone
in
the
treatment
of
various
tumors,
yet
radioresistance
often
leads
to
failure
and
tumor
recurrence.
Several
factors
contribute
this
resistance,
including
hypoxia,
DNA
repair
mechanisms,
cancer
stem
cells.
This
review
explores
diverse
elements
that
drive
radiotherapy
resistance.
Historically,
resistance
has
been
attributed
cellular
repopulation,
but
recent
research
expanded
understanding.
The
microenvironment
–
characterized
by
immune
evasion,
stromal
interactions
further
complicates
treatment.
Additionally,
molecular
mechanisms
such
as
aberrant
signaling
pathways,
epigenetic
modifications,
non-B-DNA
structures
play
significant
roles
mediating
synthesizes
current
knowledge,
highlighting
interplay
these
their
clinical
implications.
Understanding
crucial
for
developing
strategies
overcome
improve
therapeutic
outcomes
patients.
Язык: Английский