Nucleic Acids Research,
Год журнала:
2024,
Номер
unknown
Опубликована: Дек. 19, 2024
Abstract
Left-handed
G-quadruplexes
(LHG4s)
belong
to
a
class
of
recently
discovered
noncanonical
DNA
structures
under
the
larger
umbrella
G-quadruplex
DNAs
(G4s).
The
biological
relevance
these
and
their
ability
be
targeted
with
classical
G4
ligands
is
underexplored.
Here,
we
explore
whether
putative
LHG4
sequence
from
SLC2A1
oncogene
promoter
maintains
its
left-handed
characteristics
upon
addition
nucleotides
in
5′-
3′-direction
genomic
context.
We
also
investigate
this
interacts
well-established
binder,
N-methylmesoporphyrin
IX
(NMM).
employed
biophysical
X-ray
structural
studies
address
questions.
Our
results
indicate
that
d[G(TGG)3TGA(TGG)4]
(termed
here
as
SLC)
adopts
two-subunit,
four-tetrad
hybrid
left-/right-handed
(LH/RHG4)
topology.
Addition
5′-G
or
5′-GG
abolishes
fold
one
subunit,
while
3′-C
3′-CA
original
fold.
crystal
structure
analyses
show
SLC
same
LH/RHG4
solid
state
NMM
stacks
onto
right-handed
subunit
SLC.
binds
1:1
stoichiometry
moderate-to-tight
binding
constant
15
μM−1.
This
work
deepens
our
understanding
traditional
ligands.
Nucleic Acids Research,
Год журнала:
2024,
Номер
52(19), С. 11571 - 11586
Опубликована: Сен. 3, 2024
Abstract
G-quadruplexes
(G4s)
are
non-canonical
nucleic
acid
structures
that
form
in
guanine
(G)-rich
genomic
regions.
X-linked
dystonia
parkinsonism
(XDP)
is
an
inherited
neurodegenerative
disease
which
a
SINE–VNTR–Alu
(SVA)
retrotransposon,
characterised
by
amplification
of
G-rich
repeat,
inserted
into
the
coding
sequence
TAF1,
key
partner
RNA
polymerase
II.
XDP
SVA
alters
TAF1
expression,
but
cause
this
outcome
remains
unknown.
To
assess
whether
G4s
and
affect
we
first
bioinformatically
predicted
vitro.
We
next
showed
highly
stable
can
stop
at
region
from
patient-derived
fibroblasts
neural
progenitor
cells.
Using
chromatin
immunoprecipitazion
(ChIP)
with
anti-G4
antibody
coupled
to
sequencing
or
quantitative
PCR,
folded
even
when
embedded
context
G4
ligands
BRACO-19
quarfloxin
total
RNA-sequencing
analysis,
stabilisation
reduces
transcripts
downstream
around
SVA,
increases
upstream
transcripts,
while
destabilisation
using
unfolder
PhpC
transcripts.
Our
data
indicate
formation
major
aberrant
opening
way
for
development
strategies
unfold
potentially
target
disease.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 3, 2025
SUMMARY
G-quadruplexes
(G4s)
are
four-stranded
alternative
secondary
structures
formed
by
guanine-rich
nucleic
acids
and
prevalent
across
the
human
genome.
G4s
enzymatically
resolved
using
specialized
helicases.
Previous
in
vitro
studies
showed
that
DEAH-box
Helicase
36
(DHX36/G4R1/RHAU),
has
highest
specificity
affinity
for
G4
structures.
Here,
mapping
genome-wide
DNA
double-strand
breaks
(DSBs),
we
demonstrate
knockout
(KO)
of
DHX36
helicase
increases
DSB
enrichment
at
sites
presence
motif
is
a
significant
mediator
genome
instability
regulatory
regions.
The
loss
corresponds
with
upregulation
NF-κB
transcriptional
programs,
culminating
production
secretion
proinflammatory
cytokines.
Loss
expression
results
an
increase
innate
immune
signaling
stimulator
interferon
response
cGAMP
interactor
1
(
STING1
)
activation
genes
involved
pathways.
Importantly,
higher
levels
mRNA
B-cell
acute
lymphoblastic
leukemia
correlate
improved
overall
survival
relative
to
lower
,
highlighting
its
critical
role
preserving
integrity
cellular
level
context
cancer.
Cells,
Год журнала:
2025,
Номер
14(4), С. 239 - 239
Опубликована: Фев. 7, 2025
Efficient
DNA
lesion
repair
is
crucial
for
cell
survival,
especially
within
actively
transcribed
regions
that
contain
essential
genetic
information.
Additionally,
breaks
in
of
active
transcription
are
prone
to
generating
insertions
and
deletions,
which
hallmark
features
cancer
genomes.
Cockayne
syndrome
protein
B
(CSB)
the
sole
ATP-dependent
chromatin
remodeler
coupling
pathways
with
transcription,
leading
more
efficient
transcription.
CSB
best
known
its
function
transcription-coupled
nucleotide
excision
(TC-NER),
a
process
rapidly
removes
helix-distorting
lesions
stall
RNA
polymerase
II,
such
as
those
created
by
chemotherapeutic
platinum
compounds
UV
irradiation.
In
addition
NER,
has
also
been
reported
couple
homologous
recombination
Most
recently,
shown
single-strand
break
this
review,
we
will
discuss
overlapping
distinct
mechanisms
couples
these
different
We
how
functions
may
account
emerging
roles
an
innovative
target
therapy.
Proceedings of the National Academy of Sciences,
Год журнала:
2025,
Номер
122(12)
Опубликована: Март 20, 2025
During
fetal
stage,
hematopoietic
stem
and
progenitor
cells
(HSPCs)
undergo
rapid
proliferation
with
a
tight
control
of
genomic
stability.
Although
histone
H3
lysine
4
(H3K4)
methylation
has
been
reported
to
stabilize
the
genome
in
proliferating
cells,
its
specific
role
HSPC
development
remains
elusive.
In
this
study,
we
demonstrated
that
tryptophan-aspartic
acid
(WD)
repeat
protein
5
(Wdr5)-mediated
H3K4
is
crucial
for
maintaining
stability
HSPCs
zebrafish
embryos.
Loss
wdr5
led
severe
reduction
pool
caudal
tissue,
accompanied
attenuated
level
evident
p53
-dependent
apoptosis
HSPCs.
Mechanistically,
Wdr5-mediated
maintains
by
inhibiting
formation
abnormal
R-loops
HSPCs,
whereas
accumulation
exacerbates
DNA
damage.
Moreover,
absence
trimethylation
leads
an
inactivated
damage
response
(DDR)
pathway,
which
deleterious
repair
Subsequently,
found
DDR-associated
genes,
mutL
homolog
1
breast
ovarian
cancer
interacting
helicase
,
are
important
ensure
survival,
likely
stabilizing
their
genome.
summary,
these
findings
reveal
essential
through
R-loop
program
survival
