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Catalytic activities of Werner protein are affected by adduction with 4-hydroxy-2-nonenal.
[werner syndrome]
4
-
Hydroxy-
2
-
nonenal
(
HNE
)
is
a
reactive
α
,
β-unsaturated
aldehyde
generated
during
oxidative
stress
and
subsequent
peroxidation
of
polyunsaturated
fatty
acids
.
Here
,
Werner
protein
(
WRN
)
was
identified
as
a
novel
target
for
modification
by
HNE
.
Werner
syndrome
arises
through
mutations
in
the
WRN
gene
that
encodes
the
RecQ
DNA
helicase
which
is
critical
for
maintaining
genomic
stability
.
This
hereditary
disease
is
associated
with
chromosomal
instability
,
premature
aging
and
cancer
predisposition
.
WRN
appears
to
participate
in
the
cellular
response
to
oxidative
stress
and
cells
devoid
of
WRN
display
elevated
levels
of
oxidative
DNA
damage
.
We
demonstrated
that
helicase
/
ATPase
and
exonuclease
activities
of
HNE-modified
WRN
protein
were
inhibited
both
in
vitro
and
in
immunocomplexes
purified
from
the
cell
extracts
.
Sites
of
HNE
adduction
in
human
WRN
were
identified
at
Lys
577
,
Cys
727
,
His
1290
,
Cys
1367
,
Lys
1371
and
Lys
1389
.
We
applied
in
silico
modeling
of
the
helicase
and
RQC
domains
of
WRN
protein
with
HNE
adducted
to
Lys
577
and
Cys
727
and
provided
a
potential
mechanism
of
the
observed
deregulation
of
the
protein
catalytic
activities
.
In
light
of
the
obtained
results
,
we
postulate
that
HNE
adduction
to
WRN
is
a
post-translational
modification
,
which
may
affect
WRN
conformational
stability
and
function
,
contributing
to
features
and
diseases
associated
with
premature
senescence
.
Diseases
Validation
Diseases presenting
"premature aging and cancer predisposition"
symptom
werner syndrome
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