Nucleic Acids Research,
Год журнала:
2022,
Номер
50(13), С. 7260 - 7286
Опубликована: Июнь 27, 2022
R-loops
are
three-stranded
nucleic
acid
structures
formed
from
the
hybridization
of
RNA
and
DNA.
While
pathological
consequences
have
been
well-studied
to
date,
locations,
classes,
dynamics
physiological
remain
poorly
understood.
R-loop
mapping
studies
provide
insight
into
dynamics,
but
their
findings
challenging
generalize.
This
is
due
narrow
biological
scope
individual
studies,
limitations
each
modality,
and,
in
some
cases,
poor
data
quality.
In
this
study,
we
reprocessed
810
datasets
a
wide
array
conditions
modalities.
From
resource,
developed
an
accurate
quality
control
method,
reveal
extent
poor-quality
within
previously
published
studies.
We
then
identified
set
high-confidence
samples
used
them
define
consensus
sites
called
'R-loop
regions'
(RL
regions).
process,
stark
divergence
between
RL
regions
detected
by
S9.6
dRNH-based
methods,
particularly
with
respect
size,
location,
colocalization
binding
factors.
Taken
together,
work
provides
much-needed
method
assess
offers
novel
context
regarding
differences
dRNH-
S9.6-based
approaches.
Nature,
Год журнала:
2023,
Номер
623(7985), С. 183 - 192
Опубликована: Окт. 18, 2023
Abstract
The
DNA
damage
response
is
essential
to
safeguard
genome
integrity.
Although
the
contribution
of
chromatin
in
repair
has
been
investigated
1,2
,
chromosome
folding
these
processes
remains
unclear
3
.
Here
we
report
that,
after
production
double-stranded
breaks
(DSBs)
mammalian
cells,
ATM
drives
formation
a
new
compartment
(D
compartment)
through
clustering
damaged
topologically
associating
domains,
decorated
with
γH2AX
and
53BP1.
This
forms
by
mechanism
that
consistent
polymer–polymer
phase
separation
rather
than
liquid–liquid
separation.
D
arises
mostly
G1
phase,
independent
cohesin
enhanced
pharmacological
inhibition
DNA-dependent
protein
kinase
(DNA-PK)
or
R-loop
accumulation.
Importantly,
R-loop-enriched
DNA-damage-responsive
genes
physically
localize
compartment,
this
contributes
their
optimal
activation,
providing
function
for
DSB
response.
However,
DSB-induced
reorganization
comes
at
expense
an
increased
rate
translocations,
also
observed
cancer
genomes.
Overall,
characterize
how
compartmentalization
orchestrates
highlight
critical
impact
architecture
genomic
instability.
Nature,
Год журнала:
2023,
Номер
621(7979), С. 610 - 619
Опубликована: Авг. 9, 2023
Abstract
The
proper
regulation
of
transcription
is
essential
for
maintaining
genome
integrity
and
executing
other
downstream
cellular
functions
1,2
.
Here
we
identify
a
stable
association
between
the
genome-stability
regulator
sensor
single-stranded
DNA
(SOSS)
3
Integrator-PP2A
(INTAC)
4–6
Through
SSB1-mediated
recognition
DNA,
SOSS–INTAC
stimulates
promoter-proximal
termination
attenuates
R-loops
associated
with
paused
RNA
polymerase
II
to
prevent
R-loop-induced
instability.
SOSS–INTAC-dependent
attenuation
enhanced
by
ability
SSB1
form
liquid-like
condensates.
Deletion
NABP2
(encoding
SSB1)
or
introduction
cancer-associated
mutations
into
its
intrinsically
disordered
region
leads
pervasive
accumulation
R-loops,
highlighting
surveillance
function
that
enables
timely
at
promoters
constrain
R-loop
ensure
stability.
Abstract
Cancer
is
the
second
leading
cause
of
death
worldwide
and
disease
burden
expected
to
increase
globally
throughout
next
several
decades,
with
majority
cancer-related
deaths
occurring
in
metastatic
disease.
Cancers
exhibit
known
hallmarks
that
endow
them
increased
survival
proliferative
capacities,
frequently
as
a
result
de-stabilizing
mutations.
However,
genomic
features
resolve
clones
from
primary
tumors
are
not
yet
well-characterized,
no
mutational
landscape
has
been
identified
predictive
metastasis.
Further,
many
cancers
mutation
signature.
This
suggests
larger
role
for
non-mutational
genome
re-organization
promoting
cancer
evolution
dissemination.
In
this
review,
we
highlight
current
critical
needs
understanding
cell
state
transitions
clonal
selection
advantages
cells.
We
examine
links
between
epigenetic
states,
structure,
misregulation
tumor
suppressors
oncogenes,
discuss
how
recent
technologies
domain-scale
regulation
have
leveraged
more
complete
picture
oncogenic
potential.
Abstract
Eukaryotic
genomes
are
prevalently
transcribed
into
many
types
of
RNAs
that
translate
proteins
or
execute
gene
regulatory
functions.
Many
associate
with
chromatin
directly
indirectly
and
called
chromatin-associated
(caRNAs).
To
date,
caRNAs
have
been
found
to
be
involved
in
transcriptional
regulation
through
multiple
mechanisms
important
roles
different
cancers.
In
this
review,
we
first
present
categories
the
modes
interaction
between
chromatin.
We
then
detail
nascent
RNAs,
noncoding
emerging
m
6
A
on
transcription
regulation.
Finally,
discuss
cancer
as
well
epigenetic
epitranscriptomic
contributing
cancer,
which
could
provide
insights
relationship
tumor
treatment
intervention.
Genes & Development,
Год журнала:
2024,
Номер
unknown
Опубликована: Июль 10, 2024
Genome
integrity
relies
on
the
accuracy
of
DNA
metabolism,
but
as
appreciated
for
more
than
four
decades,
transcription
enhances
mutation
and
recombination
frequencies.
More
recent
research
provided
evidence
a
previously
unforeseen
link
between
RNA
which
is
often
related
to
accumulation
DNA–RNA
hybrids
R-loops.
In
addition
physiological
roles,
R-loops
interfere
with
replication
repair,
providing
molecular
scenario
origin
genome
instability.
Here,
we
review
current
knowledge
multiple
factors
that
prevent
or
resolve
consequent
transcription–replication
conflicts
thus
act
modulators
dynamics.
Frontiers in Cell and Developmental Biology,
Год журнала:
2025,
Номер
13
Опубликована: Фев. 21, 2025
R-loops
are
three-stranded
non-canonical
nucleic
acid
structures
composed
of
nascent
RNA
hybridized
with
the
template
DNA
strand,
leaving
non-template
strand
displaced.
These
play
crucial
roles
in
regulating
gene
expression,
replication,
and
transcription
processes.
However,
have
also
been
increasingly
described
as
highly
deleterious,
causing
genomic
instability
damage.
To
maintain
at
a
relatively
safe
level,
complex
regulatory
mechanisms
exist
to
prevent
their
excessive
formation.
The
growing
understanding
R-loop
functions
has
provided
valuable
insights
into
structure
potential
clinical
applications.
Emerging
research
indicates
that
contribute
pathogenesis
various
disorders,
including
neurodegenerative,
immune-related,
neoplastic
diseases.
This
review
summarizes
metabolism
its
significance
etiology
associated
disorders.
By
elucidating
governing
R-loops,
we
aim
establish
theoretical
foundation
for
disease
exploring
novel
therapeutic
strategies
targeting
these
hybrid
structures.
