Antioxidants and Redox Signaling,
Год журнала:
2017,
Номер
27(16), С. 1317 - 1331
Опубликована: Фев. 24, 2017
Proliferative
signaling
involves
reversible
posttranslational
oxidation
of
proteins.
However,
relatively
few
molecular
targets
these
modifications
have
been
identified.
We
investigate
the
role
protein
in
regulation
SAMHD1
catalysis.Here
we
report
that
is
a
major
target
for
redox
nucleotide
metabolism
and
cell
cycle
control.
triphosphate
hydrolase,
whose
function
deoxynucleotide
pools.
demonstrate
state
regulates
its
catalytic
activity.
identified
three
cysteine
residues
constitute
an
intrachain
disulfide
bond
"redox
switch"
reversibly
inhibits
tetramerization
catalysis.
show
proliferative
signals
lead
to
cells
oxidized
localized
outside
nucleus.
Innovation
Conclusions:
activity
regulated
by
oxidation.
These
data
identify
previously
unknown
mechanism
SAMHD1.
Antioxid.
Redox
Signal.
27,
1317-1331.
Chemical Reviews,
Год журнала:
2016,
Номер
116(23), С. 14379 - 14455
Опубликована: Ноя. 23, 2016
Nucleoside,
nucleotide,
and
base
analogs
have
been
in
the
clinic
for
decades
to
treat
both
viral
pathogens
neoplasms.
More
than
20%
of
patients
on
anticancer
chemotherapy
treated
with
one
or
more
these
analogs.
This
review
focuses
chemical
synthesis
biology
nucleoside,
that
are
FDA-approved
clinical
development
since
2000.
We
highlight
cellular
analogs,
drug
resistance
mechanisms,
compound
specificity
towards
different
cancer
types.
Furthermore,
we
explore
analog
syntheses
as
well
improved
scale-up
syntheses.
conclude
a
discussion
what
might
lie
ahead
medicinal
chemists,
biologists,
physicians
they
try
improve
efficacy
through
prodrug
strategies
combinations.
Cell Reports,
Год журнала:
2017,
Номер
20(8), С. 1921 - 1935
Опубликована: Авг. 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
Mitochondrial
DNA
copy
number
(mtDNA-CN)
is
an
accessible
blood-based
measurement
believed
to
capture
underlying
mitochondrial
(MT)
function.
The
specific
biological
processes
underpinning
its
regulation,
and
whether
those
are
causative
for
disease,
area
of
active
investigation.
Nature Communications,
Год журнала:
2025,
Номер
16(1)
Опубликована: Янв. 17, 2025
SAMHD1
is
a
dNTPase
that
impedes
replication
of
HIV-1
in
myeloid
cells
and
resting
T
lymphocytes.
Here
we
elucidate
the
substrate
activation
mechanism
SAMHD1,
which
involves
dNTP
binding
at
allosteric
sites
transient
tetramerization.
Our
findings
reveal
tetramerization
alone
insufficient
to
promote
hydrolysis;
instead,
requires
an
inactive
tetrameric
intermediate
with
partially
occupied
sites.
The
equilibrium
between
active
states
regulates
activity,
driven
by
dissociation
additional
ligands
preassembled
tetramer.
Furthermore,
catalytic
efficiency,
but
not
specificity,
modulated
identity
dNTPs
occupying
We
show
how
this
regulation
shapes
deoxynucleotide
homeostasis
balancing
production
SAMHD1-catalyzed
depletion.
Notably,
exhibits
distinct
functionality,
term
facilitated
depletion,
whereby
increased
biosynthesis
certain
enhances
depletion
others.
regulatory
relationship
different
sheds
light
on
emerging
role
biology
implications
for
HIV/AIDS,
innate
antiviral
immunity,
cell
disorders,
telomere
maintenance
therapeutic
efficacy
nucleoside
analogs.
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.
