Annual Review of Genetics,
Journal Year:
2017,
Volume and Issue:
51(1), P. 477 - 499
Published: Nov. 27, 2017
In
a
lifetime,
human
being
synthesizes
approximately
2×10
16
meters
of
DNA,
distance
that
corresponds
to
130,000
times
the
between
Earth
and
Sun.
This
daunting
task
is
executed
by
thousands
replication
forks,
which
progress
along
chromosomes
frequently
stall
when
they
encounter
DNA
lesions,
unusual
structures,
RNA
polymerases,
or
tightly-bound
protein
complexes.
To
complete
synthesis
before
onset
mitosis,
eukaryotic
cells
have
evolved
complex
mechanisms
process
restart
arrested
forks
through
coordinated
action
multiple
nucleases,
topoisomerases,
helicases.
this
review,
we
discuss
recent
advances
in
understanding
role
regulation
nucleases
acting
at
stalled
with
focus
on
nucleolytic
degradation
nascent
commonly
referred
as
fork
resection.
We
also
effects
deregulated
resection
genomic
instability
unscheduled
activation
interferon
response
under
stress
conditions.
Annual Review of Medicine,
Journal Year:
2016,
Volume and Issue:
68(1), P. 297 - 315
Published: Nov. 4, 2016
Type
I
interferons
(IFNs)
play
a
central
role
in
the
immune
defense
against
viral
infections.
IFN
activation
is
induced
by
pattern-recognition
receptors
of
innate
system
that
sense
pathogen-derived
nucleic
acids.
Cellular
responses
to
type
signaling
are
orchestrated
complex
network
regulatory
pathways
involve
both
and
adaptive
system.
The
genetic
molecular
dissection
rare
Mendelian
disorders
associated
with
constitutive
overproduction
has
provided
unique
insight
into
cell-intrinsic
disease
mechanisms
initiate
sustain
autoinflammation
autoimmunity
caused
disturbances
intracellular
acid
metabolism
or
cytosolic
acid-sensing
pathways.
Collectively,
these
findings
have
greatly
advanced
our
understanding
protect
organism
inappropriate
triggered
self
acids
while
maintaining
prompt
efficient
response
foreign
derived
from
invading
pathogens.
Cell Reports,
Journal Year:
2017,
Volume and Issue:
20(8), P. 1921 - 1935
Published: Aug. 1, 2017
Highlights•SAMHD1
deficiency
or
Vpx-mediated
degradation
sensitizes
cells
to
DSB-inducing
agents•SAMHD1
localizes
DNA
double-strand
breaks
in
response
damage•SAMHD1
promotes
HR
and
end
resection
independent
of
its
dNTPase
activity•SAMHD1
complexes
with
CtIP
facilitates
recruitment
damage
sitesSummaryDNA
break
(DSB)
repair
by
homologous
recombination
(HR)
is
initiated
CtIP/MRN-mediated
maintain
genome
integrity.
SAMHD1
a
dNTP
triphosphohydrolase,
which
restricts
HIV-1
infection,
mutations
are
associated
Aicardi-Goutières
syndrome
cancer.
We
show
that
has
dNTPase-independent
function
promoting
facilitate
DSB
HR.
causes
hypersensitivity
agents,
recruited
DSBs.
via
conserved
C-terminal
domain
recruits
DSBs
Significantly,
cancer-associated
mutant
impaired
interaction,
but
not
dNTPase-inactive
SAMHD1,
fails
rescue
the
impairment
depletion.
Our
findings
define
for
HR-mediated
facilitating
accrual
promote
resection,
providing
insight
into
how
integrity.Graphical
abstract
Genes,
Journal Year:
2017,
Volume and Issue:
8(2), P. 57 - 57
Published: Jan. 31, 2017
A
crucial
factor
in
maintaining
genome
stability
is
establishing
deoxynucleoside
triphosphate
(dNTP)
levels
within
a
range
that
optimal
for
chromosomal
replication.
Since
DNA
replication
relevant
to
wide
of
other
activities,
these
may
all
be
directly
or
indirectly
affected
when
dNTP
concentrations
deviate
from
physiologically
normal
range.
The
importance
understanding
consequences
genetic
disorders
disturb
levels,
and
strategies
inhibit
synthesis
cancer
chemotherapy
treatment
disorders.
We
review
here
how
abnormal
affect
discuss
the
stability.
Cell Reports,
Journal Year:
2013,
Volume and Issue:
4(4), P. 689 - 696
Published: Aug. 1, 2013
Aicardi-Goutie
`res
syndrome
(AGS),
a
hereditary
autoimmune
disease,
clinically
and
biochemically
overlaps
with
systemic
lupus
erythematosus
(SLE)
and,
like
SLE,
is
characterized
by
spontaneous
type
I
interferon
(IFN)
production.The
finding
that
defects
of
intracellular
nucleases
cause
AGS
led
to
the
concept
accumulation
nucleic
acids
triggers
inappropriate
production
IFN
autoimmunity.AGS
can
also
be
caused
SAMHD1,
3
0
exonuclease
deoxynucleotide
(dNTP)
triphosphohydrolase.Human
SAMHD1
an
HIV-1
restriction
factor
hydrolyzes
dNTPs
decreases
their
concentration
below
levels
required
for
retroviral
reverse
transcription.We
show
in
gene-targeted
mice
mouse
reduces
cellular
dNTP
concentrations
restricts
replication
lymphocytes,
macrophages,
dendritic
cells.Importantly,
absence
triggered
IFNb-dependent
transcriptional
upregulation
IFN-inducible
genes
various
cell
types
indicative
production.SAMHD1-deficient
may
instrumental
elucidating
mecha-nisms
trigger
pathogenic
responses
SLE.
Journal of Virology,
Journal Year:
2013,
Volume and Issue:
87(21), P. 11516 - 11524
Published: Aug. 22, 2013
SAMHD1
is
a
host
protein
responsible,
at
least
in
part,
for
the
inefficient
infection
of
dendritic,
myeloid,
and
resting
T
cells
by
HIV-1.
Interestingly,
HIV-2
SIVsm
viruses
are
able
to
counteract
targeting
it
proteasomal
degradation
using
their
Vpx
proteins.
It
has
been
proposed
that
dGTP-dependent
deoxynucleoside
triphosphohydrolase
(dNTPase)
restricts
HIV-1
reducing
cellular
dNTP
levels
below
required
reverse
transcription.
However,
nothing
known
about
posttranslational
modifications
potential
role
regulating
function.
We
used
(32)P
labeling
immunoblotting
with
phospho-specific
antibodies
identify
as
phosphoprotein.
Several
amino
acids
were
identified
be
sites
phosphorylation
direct
mass
spectrometry.
Mutation
these
residues
alanine
prevent
or
glutamic
acid
mimic
had
no
effect
on
nuclear
localization
its
sensitivity
Vpx-mediated
degradation.
Furthermore,
neither
nor
substitutions
significant
dNTPase
activity
an
vitro
assay.
however,
we
found
T592E
mutation,
mimicking
constitutive
main
site,
severely
affected
ability
restrict
U937
cell-based
restriction
In
contrast,
T592A
mutant
was
still
capable
restricting
These
results
indicate
may
negative
regulator
activity.
This
conclusion
supported
our
finding
hyperphosphorylated
monocytoid
THP-1
under
nonrestrictive
conditions.
