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Comprehensive analysis of LANA interacting proteins essential for viral genome tethering and persistence.
[primary effusion lymphoma]
Kaposi
's
sarcoma
associated
herpesvirus
is
tightly
linked
to
multiple
human
malignancies
including
Kaposi
's
sarcoma
(
KS
)
,
Primary
Effusion
Lymphoma
(
PEL
)
and
Multicentric
Castleman
's
Disease
(
MCD
)
.
KSHV
like
other
herpesviruses
establishes
life-
long
latency
in
the
infected
host
by
persisting
as
chromatin
and
tethering
to
host
chromatin
through
the
virally
encoded
protein
Latency
Associated
Nuclear
Antigen
(
LANA
)
.
LANA
,
a
multifunctional
protein
,
is
capable
of
binding
to
a
large
number
of
cellular
proteins
responsible
for
transcriptional
regulation
of
various
cellular
and
viral
pathways
involved
in
blocking
cell
death
and
promoting
cell
proliferation
.
This
leads
to
enhanced
cell
division
and
replication
of
the
viral
genome
,
which
segregates
faithfully
in
the
dividing
tumor
cells
.
The
mechanism
of
genome
segregation
is
well
known
and
the
binding
of
LANA
to
nucleosomal
proteins
,
throughout
the
cell
cycle
,
suggests
that
these
interactions
play
an
important
role
in
efficient
segregation
.
Various
biochemical
methods
have
identified
a
large
number
of
LANA
binding
proteins
,
including
histone
H
2
A
/
H
2
B
,
histone
H
1
,
MeCP
2
,
DEK
,
CENP-F
,
NuMA
,
Bub
1
,
HP
-
1
,
and
Brd
4
.
These
nucleosomal
proteins
may
have
various
functions
in
tethering
of
the
viral
genome
during
specific
phases
of
the
viral
life
cycle
.
Therefore
,
we
performed
a
comprehensive
analysis
of
their
interaction
with
LANA
using
a
number
of
different
assays
.
We
show
that
LANA
binds
to
core
nucleosomal
histones
and
also
associates
with
other
host
chromatin
proteins
including
histone
H
1
and
high
mobility
group
proteins
(
HMGs
)
.
We
used
various
biochemical
assays
including
co
-immunoprecipitation
and
in
-vivo
localization
by
split
GFP
and
fluorescence
resonance
energy
transfer
(
FRET
)
to
demonstrate
their
association
.
Diseases
Validation
Diseases presenting
"tumor cells"
symptom
alpha-thalassemia
carcinoma of the gallbladder
cholangiocarcinoma
cushing syndrome
dedifferentiated liposarcoma
dentin dysplasia
esophageal adenocarcinoma
esophageal carcinoma
esophageal squamous cell carcinoma
hodgkin lymphoma, classical
junctional epidermolysis bullosa
kindler syndrome
liposarcoma
lymphangioleiomyomatosis
pleomorphic liposarcoma
primary effusion lymphoma
severe combined immunodeficiency
triple a syndrome
von hippel-lindau disease
waldenström macroglobulinemia
well-differentiated liposarcoma
werner syndrome
wiskott-aldrich syndrome
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