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Structural determinants of human ζ-globin mRNA stability.
[alpha-thalassemia]
The
normal
accumulation
of
adult
α
and
β
globins
in
definitive
erythrocytes
is
critically
dependent
upon
processes
that
ensure
that
the
cognate
mRNAs
are
maintained
at
high
levels
in
transcriptionally
silent
,
but
translationally
active
progenitor
cells
.
The
impact
of
these
post-transcriptional
regulatory
events
on
the
expression
of
embryonic
ζ
globin
is
not
known
,
as
its
encoding
mRNA
is
not
normally
transcribed
during
adult
erythropoiesis
.
Recently
,
though
,
ζ
globin
has
been
recognized
as
a
potential
therapeutic
for
α
thalassemia
and
sickle-cell
disease
,
raising
practical
questions
about
constitutive
post-transcriptional
processes
that
may
enhance
,
or
possibly
prohibit
,
the
expression
of
exogenous
or
derepresssed
endogenous
ζ-globin
genes
in
definitive
erythroid
progenitors
.
T
he
present
study
assesses
mRNA
half
-life
in
intact
cells
using
a
pulse-chase
approach
;
identifies
cis-acting
determinants
of
ζ-globin
mRNA
stability
using
a
saturation
mutagenesis
strategy
;
establishes
critical
3
'
UTR
secondary
structures
using
an
in
vitro
enzymatic
mapping
method
;
and
identifies
trans-acting
effector
factors
using
an
affinity
chromatographical
procedure
.
We
specify
a
tetranucleotide
3
'
UTR
motif
that
is
required
for
the
high
-level
accumulation
of
ζ-globin
transcripts
in
cultured
cells
,
and
formally
demonstrate
that
it
prolongs
their
cytoplasmic
half
-lives
.
Surprisingly
,
the
ζ-globin
mRNA
stability
motif
does
not
function
autonomously
,
predicting
an
activity
that
is
subject
to
structural
constraints
that
we
subsequently
specify
.
Additional
studies
demonstrate
that
the
ζ-globin
mRNA
stability
motif
is
targeted
by
AUF
1
,
a
ubiquitous
RNA-binding
protein
that
enhances
the
half
-life
of
adult
β-globin
mRNA
,
suggesting
commonalities
in
post-transcriptional
processes
that
regulate
globin
transcripts
at
all
stages
of
mammalian
development
.
These
data
demonstrate
a
mechanism
for
ζ-globin
mRNA
stability
that
exists
in
definitive
erythropoiesis
and
is
available
for
therapeutic
manipulation
in
α
thalassemia
and
sickle-cell
disease
.
Diseases
Validation
Diseases presenting
"high levels"
symptom
22q11.2 deletion syndrome
adrenal incidentaloma
allergic bronchopulmonary aspergillosis
alpha-thalassemia
aromatase deficiency
cadasil
canavan disease
classical phenylketonuria
congenital adrenal hyperplasia
congenital toxoplasmosis
cutaneous mastocytosis
cystinuria
dentin dysplasia
dentinogenesis imperfecta
dracunculiasis
dystrophic epidermolysis bullosa
erythropoietic protoporphyria
gm1 gangliosidosis
hereditary cerebral hemorrhage with amyloidosis
holt-oram syndrome
homocystinuria without methylmalonic aciduria
kabuki syndrome
kallmann syndrome
liposarcoma
papillon-lefèvre syndrome
phenylketonuria
primary effusion lymphoma
primary hyperoxaluria type 1
scrub typhus
severe combined immunodeficiency
systemic capillary leak syndrome
triple a syndrome
von hippel-lindau disease
werner syndrome
wiskott-aldrich syndrome
wolf-hirschhorn syndrome
x-linked adrenoleukodystrophy
zellweger syndrome
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