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Involvement of WRN helicase in immortalization and tumorigenesis by the telomeric crisis pathway (Review).
[werner syndrome]
The
repeated
replication
of
cells
shortens
telomeres
,
culminating
in
their
instability
,
after
which
most
cells
cease
to
replicate
and
die
.
However
,
a
small
fraction
of
the
cells
become
immortalized
by
maintaining
telomeres
with
activated
telomerase
activity
.
It
has
been
proposed
that
WRN
helicase
encoded
by
the
WRN
gene
,
the
causative
gene
of
Werner
syndrome
(
WS
)
,
is
required
for
immortalization
by
the
telomeric
crisis
pathway
(
TCP
)
in
a
system
that
uses
lymphoblastoid
cell
lines
transformed
by
the
Epstein-
Barr
virus
.
Taken
together
,
these
characteristics
indicate
that
WRN
helicase
is
also
required
for
the
immortalization
of
epithelial
cells
by
TCP
and
consequent
carcinogenesis
,
suggesting
that
the
tumorigenesis
of
epithelial
cells
by
TCP
is
suppressed
in
WS
lacking
the
WRN
helicase
function
.
Notably
,
in
WS
the
pathway
of
alternative
lengthening
of
telomeres
without
activation
of
telomerase
activity
has
been
suggested
to
be
involved
in
immortalization
and
tumorigenesis
.
This
factor
is
consistent
with
the
abundance
of
non-epithelial
cancers
in
WS
in
that
the
ratio
of
epithelial
to
non-epithelial
cancers
is
approximately
1
:
1
in
WS
patients
compared
to
10
:
1
in
the
general
population
.
A
hypothetical
scheme
showing
the
role
of
WRN
helicase
in
immortalization
by
means
of
the
supposed
'
breakage-
fusion
-bridge
cycle
'
of
chromosomes
at
telomeric
crisis
is
described
.