Cell Reports,
Journal Year:
2020,
Volume and Issue:
32(7), P. 108053 - 108053
Published: Aug. 1, 2020
DNA
binding
allosterically
activates
the
cytosolic
sensor
cGAS
(cyclic
GMP-AMP
[cGAMP]
synthase)
to
synthesize
2′3′-cGAMP,
using
Mg2+
as
metal
cofactor
that
catalyzes
two
nucleotidyl-transferring
reactions.
We
previously
found
Mn2+
potentiates
activation,
but
underlying
mechanism
remains
unclear.
Here,
we
report
directly
cGAS.
Structural
analysis
reveals
Mn2+-activated
undergoes
globally
similar
conformational
changes
DNA-activated
forms
a
unique
η1
helix
widen
catalytic
pocket,
allowing
substrate
entry
and
cGAMP
synthesis.
Strikingly,
in
cGAS,
linear
intermediates
pppGpG
pGpA
take
an
inverted
orientation
active
suggesting
noncanonical
accelerated
cyclization
without
flip-over.
Moreover,
unlike
octahedral
coordination
around
Mg2+,
are
coordinated
by
triphosphate
moiety
of
substrate,
independent
triad
residues.
Our
findings
thus
uncover
activator
initiates
2′3′-cGAMP
Cancer Discovery,
Journal Year:
2019,
Volume and Issue:
10(1), P. 26 - 39
Published: Dec. 18, 2019
The
recognition
of
DNA
as
an
immune-stimulatory
molecule
is
evolutionarily
conserved
mechanism
to
initiate
rapid
innate
immune
responses
against
microbial
pathogens.
cGAS-STING
pathway
was
discovered
important
DNA-sensing
machinery
in
immunity
and
viral
defense.
Recent
advances
have
now
expanded
the
roles
cancer.
Highly
aggressive,
unstable
tumors
evolved
co-opt
this
program
drive
tumorigenic
behaviors.
In
review,
we
discuss
link
between
antitumor
well
cancer
progression,
genomic
instability,
tumor
microenvironment,
pharmacologic
strategies
for
therapy.
SIGNIFICANCE:
defense
infections.
Given
its
role
activating
surveillance,
it
has
been
assumed
that
primarily
functions
a
suppressor.
Yet,
mounting
evidence
suggests
depending
on
context,
signaling
can
also
metastasis-promoting
functions,
chronic
activation
paradoxically
induce
immune-suppressive
microenvironment.
Science,
Journal Year:
2019,
Volume and Issue:
363(6431)
Published: March 8, 2019
DNA
is
highly
immunogenic.
It
represents
a
key
pathogen-associated
molecular
pattern
(PAMP)
during
infection.
Host
can,
however,
also
act
as
danger-associated
(DAMP)
and
elicit
strong
inflammatory
responses.
The
cGAS-STING
pathway
has
emerged
major
that
detects
intracellular
DNA.
Here,
we
highlight
recent
advances
on
how
cGAS
STING
mediate
responses
these
are
regulated,
allowing
cells
to
readily
respond
infections
noxious
agents
while
avoiding
the
inappropriate
sensing
of
self-DNA.
A
particular
focus
placed
role
in
context
sterile
conditions.
Manipulating
or
may
open
door
for
new
therapeutic
strategies
treatment
acute
chronic
inflammation
relevant
many
human
diseases.
Annual Review of Biophysics,
Journal Year:
2020,
Volume and Issue:
49(1), P. 107 - 133
Published: Jan. 31, 2020
Many
biomolecular
condensates
appear
to
form
via
spontaneous
or
driven
processes
that
have
the
hallmarks
of
intracellular
phase
transitions.
This
suggests
a
common
underlying
physical
framework
might
govern
formation
functionally
and
compositionally
unrelated
condensates.
In
this
review,
we
summarize
recent
work
leverages
stickers-and-spacers
adapted
from
field
associative
polymers
for
understanding
how
multivalent
protein
RNA
molecules
drive
transitions
give
rise
We
discuss
valence
stickers
impacts
driving
forces
condensate
elaborate
on
can
be
distinguished
spacers
in
different
contexts.
touch
impact
sticker-
spacer-mediated
interactions
rheological
properties
show
model
mapped
known
drivers
types
Annual Review of Genetics,
Journal Year:
2019,
Volume and Issue:
53(1), P. 171 - 194
Published: Aug. 20, 2019
We
have
made
rapid
progress
in
recent
years
identifying
the
genetic
causes
of
many
human
diseases.
However,
despite
this
progress,
our
mechanistic
understanding
these
diseases
is
often
incomplete.
This
a
problem
because
it
limits
ability
to
develop
effective
disease
treatments.
To
overcome
limitation,
we
need
new
concepts
describe
and
comprehend
complex
mechanisms
underlying
Condensate
formation
by
phase
separation
emerges
as
principle
explain
organization
living
cells.
In
review,
present
emerging
evidence
that
aberrant
forms
condensates
are
associated
with
diseases,
including
cancer,
neurodegeneration,
infectious
examine
driven
condensates,
point
out
opportunities
for
therapeutic
interventions.
conclude
provides
useful
framework
understand
fight
some
most
severe
Genes & Development,
Journal Year:
2019,
Volume and Issue:
33(23-24), P. 1619 - 1634
Published: Oct. 8, 2019
The
idea
that
liquid–liquid
phase
separation
(LLPS)
may
be
a
general
mechanism
by
which
molecules
in
the
complex
cellular
milieu
self-organize
has
generated
much
excitement
and
fervor
cell
biology
community.
While
this
concept
is
not
new,
its
rise
to
preeminence
resulted
renewed
interest
mechanisms
shape
drive
diverse
self-assembly
processes
from
gene
expression
division
stress
responses.
In
vitro
biochemical
data
have
been
instrumental
deriving
some
of
fundamental
principles
molecular
grammar
biological
separate,
basis
these
interactions.
Definitive
evidence
lacking
as
whether
same
apply
physiological
environment
inside
living
cells.
Perspective,
we
analyze
supporting
vivo
across
multiple
processes.
We
find
for
LLPS
often
phenomenological
inadequate
discriminate
between
other
possible
mechanisms.
Moreover,
causal
relationship
functional
consequences
are
even
more
elusive.
underscore
importance
performing
quantitative
measurements
on
proteins
their
endogenous
state
abundance,
well
make
recommendations
experiments
yield
conclusive
results.
