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ANALYTICAL
REVIEW
RNA-Dependent
DNA
Polymerase
Views
.
B
the
NOW
fact
that
on
the
By
ROBERT
some
Current
C.
The
virologists
to
trait,
a characteristic
genetic
plasia,
Temin
explain
how
that
efforts
synthesize
from
cell
without
the virus
itself
carrying
DNA.
to explain
this phenomenon,
involved
diary
using
Woul(l
then
the
viral
formation.
thesis
of new virus
a DNA
intermediate,
)
viruses
cepts
Bader,2
the
is
,
at
RNA
the
basis
time
and
was
as
had
did
concept
as Ten3in
Front
the
R. C.
Institute,
GALLO,
National
Abbreviations
leukemia;
cells
gain
virus;
AMV,
consisting
of
homopolymers
by
inhibited
RNA
tumor
to
viruses
based
for
Institutes
much
the
most
of
D
the
a reaction
of cells
by RSV
in S phase
of the
contain
Health,
Section
in text:
ALL,
acute
lymphocytic
polymerase
Rauscher
avian
on
Cellular
Bethesda,
new
DNA,
However,
of the
part
the
evidence,
on
inhibitor
Bethesda,
Md.
lymphohlastic
leukemia;
Mechanisms,
National
leukemia;
CML,
chronic
acute
AML,
myelocytic
leukemia;
( “Reverse
Transcriptase”
) ; DDDP,
leukemia
virus;
MSV, murine
sarcoma
myelohlastosis
or
Control
oligomers
virus;
of
Cancer
Md.
rA.dT,
rihoadenylate
the
and
myelohlastic
RDDP,
DNA-dependent
virus;
RSV,
Rotis
synthetic
RNA-DNA
deoxythymidylate;
RNA
duplex
consisting
of homopolymers
of riboadenylate
the synthetic
DNA
duplex
consisting
of homopolymers
of
deoxyguanylate;
d( AT),
the synthetic
DNA
consisting
of an alternating
Blood,
of
actinomycin
RNA
virus,
proposal.
(1 )
con-
Temin,1
involved
this
because
these
replication
used
is an
replication
support
National
of Hraltli,
synthetic
dC.dC,
and
for
example,
that
infection
that
synthesized
initially
Institute,
D
viral
approval
indirect,
: head,
DNA
RLV,
sarcoma
of
lent
widespread
Institutes
chronic
RNA-dependent
DNA polymerase;
stage
RNA,5
support
for
DNA
transin syn-
1.971.
M.D.
used
CLL,
some
The
this
viruses
through
do other
RNA
( as
the concentrations
reactions,
and RSV
The
observations
different
from
that
tumor
information;
actinomycin
at
transformed
Cancer
25,
that
.
viral
was
National
June
that
with
realized,
Submitted
shown
neo-
for neoplastic
be involved
intermediate
hypothesis.
namely,
proposed
of RNA
RNA
indirect
Since
DNA-templated
that
not
on
( RSV )
made
synthesis
an
cell,
other
a stable
proposed
in 1964 by
of a DNA
interme-
and account
would
also
of replication
provirus
based
template.
of DNA
cell cycle4
and
which
hybridizes
idea
through
of the
was
others3
speculation
using
DNA
This
not
some
produce
to daughter
further
genome
DNA
poly-
established.
and
could
The idea,
the synthesis
Temin
into the host
the integrated
RNA.
Rous
sarcoma
virus
specifically
inhibits
requires
as template.
be integrated
Furthermore,
is well
Temin
virus
tumor
( DNA
DNA
)
of 1-loward
RNA
passing
Cells:
State
( RNA-dependent
an
and
GALLO
enzymes
merases
) can use RNA templates
story,
of course,
began
with
the
tumor
in Viruses
hybrid
rA.rU,
the
and
ril)ouriclylate;
deoxycytidylate
and
copolymer
of dA
dT.
Vol. 39, No. 1 (January),
1972
117
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118
ROBERTC.
experiments,
and
in the
However,
and
(2 )
and
not
findings
Mizutani6
of
an
extended
in several
laboratories,
concept
every
of
especially
this
were
those
process
1970
in
at
Temin
quickly
least
their
RSV
and
in
confirmed
of Spiegelman59
involves
new
published
( RDDP)
findings
was
in June
independently
polymerase
These
.
concept
biology.
biologist,
Baltimore7
( RL\T )
the
molecular
to almost
DNA
virus
important,
bacterial
David
RNA-dependent
current
more
of
known
and
leukemia
Rauscher
is perhaps
scheme
as it is now
Satoshi
The
what
traditional
GALLO
and
two
steps,
and
Green.1#{176}
as
shown
below:
RNA
7OSRNA
DNA
.4
-
DNA
The
precise
mechanisms
synthesis
result,
established.
70S
of
DNA
It appears
RNA
Both
ably
arise
from
from
that
the
saturated
added
DNA
not
as yet
and
of
P.,
effective
( see
the
first
here
that
evidence
for
fact, part
synthesis
of the virus internal
of double-stranded
also
principle
be
until
very
contained
OF
of
et al.14
the
end
as
entire
Both
that
the
evidence
RLV
activity
is
is
viral
is
( “Endo-
reaction.
the
RNA-
structure
)
RNA.
After
syn-
the DNA
is thought
to
Temin
and his colleagues12
( endonuclease
)
If these
latter
activities
events
into
required
the cell
exonuclease.15
activities
indicates
is an
a hybrid
endogenous
from
prob-
polymerase
when
DNA
polymerase
since
the hybrid,
Recently,
have
are
results).
virion
expected
synthesis
“REVERSE
virus
have
the
( the
two
is valid
for
RNA
viruses
sclerosis
for
information
unpublished
“machinery,”
DNA
and
RNA
recently,
Schlom
the
activities
separated.
purified
in the
for
a DNase
and
40. Thirty-three
viruses.
Of
tiple
recent
et al. that
to indicate
suggestive
proposed
to DNA
not to have
oncogenic
potential
agent
of a chronic
neurological
by Temin
duced
by
but
the
considered
,
then all the
its integration
and
also
be
provided
are,
in
for the
genome
accomplished.
number
is at least
oncogenic
the
DNA
from
cell’s genome.
ligase
DisTRIBu-rIoN
total
be
polymerase
R.,
is to he
of
refers
reported
RSV
This
step
double-stranded
into the host
a DNA
Gallo,
templates
).
below
can
been
there
is no evidence
catalytic
site,
and
M.,
reaction”
and,
have
most
thesis
of
integrated
The
DNA-dependent
and
one
Sarin,
)
below
RNA,
of Duesberg
of the
genous
RDDP
known
work
( Reitz,
hybrid
in
70S
e.g., when
partially
there
is no increase
product
can
virus
are the same,
RNA template
One
DNA
elegant
DNA
( see
debatable
DNA.11
activities
one protein,
more
than
sites
with
the
and
These
very
the
into
RNA-dependent
detected.
still
from
from
is transcribed
been
the
are
TRANSCRIPTASE”
systems
suggested
Foamy
( Table
disease
an
now
virus
positive,
four
are
and
Visna
1 ) . The
Visna
in sheep.
However,
also be
stable
investigation
of this type
of enzyme
that even
the Visna
RNA
examined
of the 40 were
remaining
six,
neoplasia,
it might
that
also
involve
presence
indicates
IN
VIRuSES
for
the
presence
of
and of these,
27 are
probably
oncogenic
virus
)
were
thought
virus
is the causative
if the idea initiated
valid
for other
disorders
ingenetic
alterations.
Indeed,
of tissues
of patients
with
mul-
activity.
In any event,
very
virus
is capable
of producing
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DNA
119
POLYMERASE
Table
1.-Summary
of RNA
Viruses
Containing
vinis
Viruses
of
Known
Polymerase
Source
Oncogenic
Activity
Potential
Rotis sarcoma
(RAV-1)
CEF#{176}
(Prague)
(Schmidt-Ruppon,
Avian
leukosis
(Mc
Avian
reticuloendotheliosis
(Twiehaus
agent)
Avian
DNA
B-77)
29)
Cell
culture
( chicken)
Cell
CEF
culture
(chicken)
CEF
Chicken
myeloblastosis
+
+
+
+
+
+
+
plasma
Culturedmyeloblasts
Murine
leukemia
Rauscher
Plasma
Rauscher
Rauscher
MEF
JLS-V5
AKR
Cell
Moloney
JLS-V9
Murine
sarcoma-leukemia
+
+
+
+
+
t
cell
culture
line
(rat)
cell
line
complex
Moloney
Mouse
Moloney
Moloney
MEF
78A1
Harvey
MEH
Kirsten
NRK
Paris
rat cells
mouse
cells
cells
R III milk
C3H
milk
Ricard
Cell
culture
(feline)
Thielen
Cell
culture
(feline)
Gardner
Cell
culture
( canine)
Cell
culture
(marmoset)
Cell
culture
(feline)
Cell
culture
B34
LSH
hamster
(canine)
cells
Murine
Feline
mammary
tumor
Gardner
Hamster
sarcoma
Hamster
leukemia
virus
C-Type
and/or B-Type
Mammary
tumor
Mammary
Viper
Viruses
tumor
of Unproven
)
( Mason
( human
tumor
Nononconegic
)
(A
Reo
Vesicular
stomatitis
and
+
+
+
+
+
cells
culture
+
+
+
+
+
cells
( monkey)
cells
plexus
cells
(sheep)
milk
fluid
fluid
L-cells
cells
cells
BHK
HeLa
Allantoic
Respiratory
0 CEF,
rat
Cell
Allantoic
Allantoic
WSN)
Polio
Sendai
the
R35
Human
disease
Influenza
with
+
+
+
Viruses
Newcastle
USA
hamster
vsw
Choroid
Mammary
Taken
+
+
+
Oncogenicity
Visna
Sci.
+
leukemia
Feline
sarcoma
Ricard
Gardner
Simian
+
+
+
tumors
HEP-2
syncytial
foamy
from
68:
J., Hatter,
Schlom,
permission
chick
Monkey
virus
182,
1971,
with
of the
embryo
fluid
cells
authors
fibroblasts;
D.
slight
H.,
Burny,
additions
and
f
and
A.,
kidney
and
slight
Spiegelman,
modification,
publishers.
MEF,
mouse
embryo
fibroblasts.
+
S. Proc.
and
Nat.
reproduced
Acad.
here
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
120
ROBERT
neoplastic
L.
transformation
J.
B.,
Virol.
preseice
of
Foaiiit,
virus.
In
virion
reverse
RDDP
Three
recent
illustrate
to
D.
des
and
contain
colleagues’5
have
shown
particles
morphologically
tumors.
)
of
the
recent
adds
the
support
etiology
the notion
concept
that
that these
they
may
milk
reportiR
conclusions
( personal
of
from
the
to
the
the
virus-
patients
to the
analysis
that
of the
can
he
that
these
parti-
I)rOduct
drawn,
viruses
with
B particles
indicates
particles
are
be oncogenic.
communication
fraction
product
dependent
Examination
for
RNA-dependent
sera
has
and
of the
DNA
been
antigen
Cell
of the
this
report
obviously
acids
does
Anderson
C virus
tumor
in cells
type
produced
do
finding
)
detected
has
high-speed
centri-
hepatitis.
Detailed
analthe reaction
apparently
but
RNA
endogenous
to the
fractions
from normal
Lack of any polymerase
Kiessling
et
DNA
polymerase
indeed
contain
RDDP
of this
American-Burkitt
particles.
by
17
after
al.’5
but
has
is detectable
is this particle
is obviously
partic-
sera
were
activity
not
been
our
in some
normal
an RNA tumor
of great
importance.
has just
a pleural
published
effusion
particles,
which
C Particle
The
M. D.
ings of a type
successfully
RNA,
particulate
polymerase.
reported
reference
antigen-positive
completed,
on a natural
( DNA-dependent
Confirmation
and
( obtained
of plasma
with
Australian
has not yet been
fraction.
“Human”
not
cross-react
antigen
of
mouse
particles
shown
a polymerase
is
line
specific
some
The
( ESP-1
)
antigens
recent
established
of rat,
indication
of
are
from
hamster,
of
their
finda patient
now
the
being
original
or cat-type
cross-reactivity
Cwith
virus
( Gilden,
R. : personal
communication).
studies
indicate
that the cell line is indeed
human.
with
the Texas
group,
we have
found
RDDP
activity
by
is present
purified
detergent-dependent
group
from
leukemia
immunologic
study
utilizing
a cell
with
there
virology
obtained
lymphoma.2#{176}
from
However,
Karyotype
and
In a collaborative
sensitive,
A
additional
to be
normal
Cs-i
is
humans
helping
in
assay
and
in
similar
Although
experience.’9
sera ) . If this
source,
from
enzyme
that
definitive
of patients
shown
with
role
before
in a particulate
virus?
obtained
this
a virus
a
1)OterItiai
the
Antigen
fugation
in
his
Hirschman
negative
fact,
play
activity.
supports
to the
tilate
is, in
may
Stone,
of
“ViRUSES”
in particles
RDDP
certainly
credence
yses
TUMOR
needed
is
was
a particle
mammary
reaction
S.
HUMAN
of
and
exception
(111(1 oncogeni-c
usefulness
K.,
known
activity
activity
major
particle
contains
mouse
RDDP
presently
“B Particle”
cancer
Australkin
cells
only
FOR
of RDDP
( Takemoto,
mouse
the
CANDIDATES
whether
Moore
produce
normal
that
for
that
the
disease.
Milk
breast
IN
potential
determine
possil)ility
associated
of
so
transcriptase
findings
the
Human
)
press
C. GALLO
equilibrium
which
DNA
gradient
catalyzes
synthesis
centrifugation.
out
that
an
\Ve
endogenous,
is restricted
to the
have
RNasei.i5-i.16
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DNAPOLYMERASE
density
121
region
The
same
virus.2’
It
(1)
of
a sucrose
enzyme
readily
will
obviously
whether
pliotna
he
that
inhibit
this
with
have
found
other
is indeed
human.
FROM
LEUKEMIC
no case was endogenous,
RNase-sensitive
observed.
All activity
was either
dependent
hybrids,
or if endogenous
activity
was
RNA-DNA
patients
that
with
the
with
DNase
but
high
white
cell
polynierase
activity
similarly
This
reported
preparation
when
the
isopyknic
RNA
sensitive
DNA
polynerase
showed
activity
polynlerase
activity
the
virus
core
activity
assays
PreParation
this are
l)ut
for
viral
preparation
Not
of
to “solubilize”
markedly,
but
of
the
enzyme
The
DNA
assays
added)
served
viral
added
DNA,
by
that
some
the
plates
superior
do
however,
cellular
may
templates
provide
to
in
mean
ploymerase
lib-
with
CLL.
Of interest,
was
density
analyzed
region
no
by
where
endogenous
the
RNase-
adhere
care
and
or
to the
ancillary
taken
that
difficulties
of
common
outer
the
virus
achieving
contaminants,
envelope.
However,
jnvolves
treatment
with
generally
increases
enzyme
range
is narrow.
agents
allow
templated
or an
RNA-DNA
and
High
for
it
a nonionic
activity
concentra-
“solubilization”
of
and
RDDP
information
one
Synthetic
and
their
homopolymers
polyribonucleotide
than
about
the
endogenous
the
( no
reaction
exogenous
hybrids.
Temi&2
synthetic
the
be
This
These
double-stranded
strand
VIRUSES
components.
Spiegelman9
for
the
IN
usually
activity.
RNA,
must
fragments
concentration
the
RDDP
FOR
al.23 that
the polymerase
of tumor
viruses
is
of the virus,
not with
outer
components.
The
enzyme.
structural
polydeoxyribonucleotide
far
fraction
found;
either
measure
an endogenons
utilizing
the virus 70S RNA
introduced
noted
findings
DNA
in the
ASSAYS
polymerase
inhibit
from
How-
particularly
these
particulate
are
et
acceptable
detergent
utilizing
were
the
leukemic
activity.22
was
banded
contaminants,
enzymes
viral
the
several
detergent-dependent
DNA
on the addition
of DNA,
found
it was destroyed
by
interpret
activities,
only
by Cerwin
the “nucleoid”
detergent
tions
OF
of cellular
even
shown
with
of
activity
in sera of two patients
exogenous
DNA
templates.
are
similar
C-particle
and
(3)
associated
with plasma
membranes
an RNA
tumor
virus.
Kiessling
et al.18
the
POh’nlerase
known.
apparently
has been
associated
of
sera
DNA-dependent
activity
AsPEers
is free
vell
with
of
human
patients;
polymerase
Activity
We
role
lym-
reported.
PRAcrIcAI.
In
RNase.
from
particles
was
DNA
cells, probably
and not from
centrifugation
tumor
not
counts.
was
erated
from
dead
or dying
or other
cellular
fragments
contain
things
with
SERUM
from
ever,
in
synthesis
preincubation
a
virus
fractions
)
CML
leukemia
other
1)atieilts
by the
cancer
the
particulate
other
made
human
from
C-particles).
feline
suggesting
DNA
( ALL,
and
intact
the
among
from
patients
AML,
of
from
determine,
thereby
the
FRACFION
that
to
in sera
whether
whether
PARTICULATE
\Ve
found
RNA
certainty
acid
now
polymerase,
(2 )
I)drticles
in these
I)atiellts;
svill hyl)ridize
with
cellular
to determine
be
typical
nucleic
important
can
antibodies
( density
gradient
utilizes
nature
RNA
templated
or
reaction
hybrid
templates
associates.
They
containing
obone
( e.g.,
rA.dT)
were
RNA.
These
tem-
of the
enzyme,
and
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
122
the
since
virus
indicators
RDDP
of
activity.
for
preliminary
Spiegelman24
cells,
It
has
this
affinity
comparison
I and
these
for
of
the
the
DNA
used
AMV
that
template
use
the
RNA
activity
RDDP
strand
an
(2 )
cate
polynler
( 3)
proof
density
the
also
and
and
strands
is RNA.
been
of virus
he
established
example,
for
it has
can
one
be
to
very
that
although
with
not
after
many
years
RNA
of DNA
activity
in tumor
on
show
After
to
examine
excephave
will
procedures,
proof
of a virus
of a deoxynucleotide);
activity
detergent
complementarity
(6 )
to
demonstrate
reported
FUNCTION
OF
polymerase
that
bands
in the
treatment.
It would
between
that
one
the RNA
of the two
to contain
RDDP
particles
on the
E. coli
a
not
activity;
human
for
sources,
RDDP
VIRUS
in RNA
from
that
tumor
viruses,
of course,
DNA
polymerase
sugIn
supRSVa
( 0),
However,
I, its biologi-
whole
bacterium
remains
uncertain.
More
information
will
from
studies
with
mutants,
as well as perhaps
the use of
before
we can
be certain
of tile role
of this
enzyme
formation
or in cell
PRESENCE
Neoplastic
the
i.e., an RNA-dependent
triphosphates
( to mdi-
addition
depends
virus
of investigations
in the
have
to be obtained
selective
inhibitors,
function
the
with the first three
criteria
established
it is possible
contain
small
amounts
of DNA2#{176}thereby
enhancing
polymerase
reaction.
The last two objectives
have
every
a
strand,
Conversely,
gests
a role for the enzyme
in initiation
of neoplastic
transformation.
port
of this, Hanafusa27
has shown
that
a mutant
of RS\
termed
which
has no infectious
capacity,
is lacking
in polymerase
activity.
cal
In
polymerase
in screening
polymerase
not yet been
established
for the
certain
that these
are in progress.
presence
relatively
specific.
DNA
polymerases
cells ) and most
useful
terminal
and
own.
transcriptase”
in any virus
it would
would
include:
( 1 ) demonstration
( 4)
(5 )
product
BIoLoGIcAL
The
just
that
desirable
DNA
Even
preparations
DNA
some
virus
DNA-dependent
not
have
ribohomopolymer
strand.
is certainly
by
in
our
DNA
showed
purified
proliferating
and
used
activity
from
coli
is RNase
sensitive,
all four deoxynucleoside
is DNA;
does
far
Escherichia
though
of a “reverse
requirement
that
and
deoxyribohomopolymer
Therefore,
for
product
the
any
sensitive
very
including
are
Baltimore25
is not specific
of any RDDP.
reaction
formation
template
use
be
enzyme
RDDP
they
several
partially
or neoplastic
of rA.dT.
characteristic
obviously
but
not
hands,
normal
requirements
that
related
laboratories
virus
of
AMy,
can
C. GALLO
advocated
or
other
templates,
of
templates
matter
endogenous
this
the
they
been
enzyme
will “read”
off the
for the deoxyribohomopolymer
establish
the presence
that
a minimum
initial
reaction;
for
preferences
will
In our
( from
with these
or for that
To
seem
of
polymerase
them,
have
although
polymerase
of poly dC.
examined
for
they
in several
synthetic
coli DNA-dependent
it has
marked
preference
tion
been
fact,
searches
E.
the
affinity
In
and have now l)een
is now
quite
clear
great
great
ROBERT
OF
growth.
RDDP
IN
CELLS
Cells
the
reports
of RDDP
in
cells,
and in particular,
RNA
human
oncogenic
leukemic
viruses,
cells,
it
for
was
the
of
interest
presence
of
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
DNAPOLYMERASE
123
this type
of enzyme.
index
of the presence
First,
for the obvious
reason
that
of an RNA
tumor
virus
or virus
eating
tumor
a role
even
of RNA
if RDDP
presence
differences
ences
of
viruses
is present
hut
an analogous
in RNA
species
might
be involved
in the
is not
normal
faulty
abundant
in the
activity
protovirus
possible
previously
that this
simply
was general
activity
because
it had not
conditions.
investigation
and
of
leukemic
the
properties
( purely
host
involved
or
characterized
of
These
),
originated
or
these
( greater
high
count
inhibited
by
rifampicin
hemagglutivin
normal
is no
CLL
leukemic
We have
cells
also
polymerase(
leukemic
not
we
indicate
have
the
existence
of
nature
cells
an RNA
tumor
we
source.
virus.
are
)
feel
The
thetic
mic
extracts
to show
endogenous
and
Its
presence,
There
are,
that
four
using
crude
synthesis
natural
there
that
key
purified
both
templates
of these
was
The
a
is no
cells
destroyed
normal
in
cytodifferentiation.
RNA
normal
labora-
not
tumor
viruses.
not
We
that
the
DNase
template.
but not
achieved
normal
of
is
mi-
and
as synleuke-
in at least
for the presence
of
Temin.3#{176} The approach
treatment
the
is present
templates
as well
results
with human
been
the
between
activity
now
( but
does
prove
triphosphates,
natural
of these
control
activity
does
DNase
destroys
by sensitivity
to
by
AML
that other
later
our
not
has
lym-
( For
and
and
similarities
an
blood
the
of RDDP
from
by
and metabolic
activnormal
lymphocytes
in
therefore,
cells
not
perfect
systems
role
however,
activity
but
above
presence
In addition,
evidence
has been
reported
by
extracts
the
been
ALL.345
deoxynucleoside
the enzyme
used
RNA.
Confirmation
iahoratories.”M
neoplastic
cells
DNA
all
to be
peripheral
for
play
RNA.
RNase
but
is DNA
as shown
requires
that
double-stranded
cell
three
other
in infected
was
reaction
showed
specific
not found
in phytoWe feel that
the best
normal
in morphology
of activity
mere
on
we
was
in the
the
dependent
The
product
RNase.
normal
host
ALL.
of the assay
Baltimore,3”
leukemic
cells
and
those
obtained
able to show
that from leukemic
tially
human
likely
untreated
Although
that
RDDP
of
have
been
exogenous
synthesized
of
previously
lymphocytes
that
of its
expericomparative
specific,
are
activity
lymphocytes.
comparable
that
lack
stressed,12aa
described
N-demethylrifampicin,
might
have been
due to limits
of sensitivity
cells
might
contain
this activity.
Temin,35
tory31’2
suggested
that
this
activity
might
Finally,
)
mm
control.
are at least
emphasized32
s)
virus
not
as
it was
appropriate
systematic
of both
a similar
normal
cells,
a
and have
systems.
PHA-stimulated
leukemic
or an altered
not
under
whether
iOO,000/cu
comparable
human
latter,28t
polymerases,
for
begin
DNA
the
account
for
These
differ-
neoplastic
transformation
( see below ) . Third,
DNA
to
Second,
enzyme,
RNA-dependent
DNA
polymerase
activity
from lymphoblasts
of three
patients
with
time
for
and
available
for
and
ity.
comparisons
for
of the
all
derivative,
At that
( PHA)-stimulated
cell
control
than
rifampicin
itself.’2
phocytes
there
the
might
cells.
time
of growth
cellular
Last year we reported
detecting
in partially
purified
extracts
prepared
very
was
leukemic
cells
and leukemic
a combination
in regulation
in
virus
looked
the
disease.
tumor
been
enzymes,
be a sensitive
thereby
impli-
of the
the
produce
of Temin
of
it was
leukocytes.
proteins
well
in cells might
hypothesis
Fourth,
as
maturation
or more
suggested
mental
same
in
between
in the
pathogenesis
the
polymerase
it might
product,
cellst9
)
the
crude
RDDP
used
showed
cell-
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
124
ROBERTC.GALLO
ular extract
with RNase
prior
to the initiation
of polymerase
and associates4#{176} examined
a wide
range
of biological
systems
double-stranded
polydeoxyribonucleotides,
the homopolymers
DNA
hybrid
rA.dT/dC.dG
exception
leukemic
kemia
rA.dT,
and
tissue
culture
activity
with
consistently
cells
early
found
subsequent
investigations
have started
with
of this activity
templates
as well
all solid tumors,
communication
),
have
primarily
to state
templates
what
are
whether
the
percentage
simply
except
showed
from
ever
same
we have
fraction
the
one
)
acute
this
.
higher
with
Virtually
the
all
monocytic
relatively
leuhigh
that
CelLc
the sensitivity
several
laboratories
suggest
the
human
leukopartial
natural
With
these
of
out
of
use
with
of rA.dT
it is not certain
low activities
are
the
rA.dT
carried
RDDP,
not
assumed
to be
template
was
soon
apparent.
rA.rU
with
the established
human
fibroblasts
since
Scolnick
nontransformed
in culture
and
et
are
enzyme
after
the
lack
So far
RDDP
when-
partial
the
became
data that
purification.
has found
abundant
cells.
Similarly,
we
However,
these
of specificity
al. noted
activity
mouse
cell line
concluded
dis-
templates,
of the virion
RDDP
to find preliminary
especially
RDDP
an
natural
For example,
Spiegelman
et al.4#{176}
stated
that his laboratory
activity
in embryos
at early
stages
as well
as neoplastic
noted
activity
with
rA.dT
in normal
human
lymphoblasts.3435
were
by
reaction.
with
rA.dT.
for detection
this template
results
whether
natural
are missed
) or
out
directed
activity
with
our
and his colleagues.
With
RNA,
or mammalian
28S
However,
it is premature
( and
having
activity
rA.dT
utilized
presence
since
templates
carried
the
of Spiegelman
MS2,
reovirus
more
restricted.
are positive,
too insensitive
obtained
fractions
has always
showed
When
known,
remained
templates.
with
Normal
with
cells,
quantity
of cells and have attempted
case. We have
sought
activity
with
with
those
e.g., phage
are much
just
reactions
tinct
a large
in each
as synthetic
essentially
in agreement
natural
RNA
templates,
RNA,
our positive
findings
activities
much
than
with
normal
embryos
( see below
rA.dT.
cytes.
We
purification
might
have
neoplastic
cells and
cells and
S., personal
( Spiegelman,
Our
apparently
ratios
with
of tissue
culture
assay.
Spiegelman
utilizing
synthetic
dC.dC,
and the
with
with
rA.dT
and
and
( BALB/3T3)
activity
was
this
present
in normal
cells in tissue
culture.41
With
the exception
of a recent
preliminary
report
by Penner
et al.,38 there
are no published
data
to indicate
the existence
in normal
cells
of RDDP
capable
of using
natural
templates,
and in this one
report
template
instruction
by single-stranded
RNA
was
not shown
and
it
would
not
addition
be
firmed
our
CLL.
If the
implications
lion.
lated
determined
enzyme
findings
from
a true
of
findings
in normal
recently
than
This
new
double-stranded
the
data
presented
polymerase.
RDDP
to theories
We have
lymphocytes
preparations.
templates,
or
in
ALL
and
authors
extended
lymphocytes
of information
whether
These
are
transfer
these
verified,
with
this
state
RNA
was
a terminal
they
have
positive
they
for
will
conto
findings
have
antibody
strong
forma-
found
considerably
more
activity
from
PHA-stimuwe previously
reported,
using
more
purified
enzyme
activity,
but
although
so far not
stimulated
by some
with any single-stranded
natural
RNA.
RNA
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
DNAPOLYMERASE
IS
THE
125
ENZYME
The
IN
answer
to this
easy to establish.
( i ) the polymerase
salt
SOME
ever,
this
approach
are
completely
( cell
factors
as emphasized
tumor
virus
found
be
)
RDDP
reaction.
This
(3 )
very
recently42
from
viruses,
activity
hybrid
No
one
RNA
endogenous
virus
705 RNA
i.e., the RDDP
et
milk
these
less
greater
has
shown
that
RNA
tumor
anyone
found
success
the
DNA
purified
cellular
the single-stranded
destruction,
cellular
cellular
these
in
polymerases
virus
while
705
RNA
nucleases
must
RNA
)
removed
or RLV
from
even
the
P.,
\Vasserman,
The
possibility
that
a contaminating
and
necessary
for the reaction
to initiate
the reaction
is RNase
sensitive,
indicating
it serves
as a primer
while
the RNA
acts
.
by not
Moreover,
requiring
of activity.
from
be
P.
,
its
tumor
was shown,
RNAs
from
for loss
can
RDDP
of the
RNA.
As stated
to be capable
until
it from
polymerase
activity.
susceptible
to
we
cells
not
with
addition
polym-
tumor
separate
nucleases
before
with
705
appear
( Sarin,
as template
of
about
RNA-directed
chances
traces
from
enhanced
some
specificity
RNA
rather
than
still retaining
is extraordinarily
be
differ
we are obviously
handicapped
human
RNA tumor
virus.
of course,
more
complex,
all
Further-
from
virusbe the case.
However,
with
greater
removing
and
of a human
as some
of the
AMV
this
a
with
to
only
completely
synthesis
consequently
difficulty
RDDP
lacks template
activity
(leukemic
) DNA polymerases
single-stranded
preparation
present
However,
is present
and
with
virus
(2 )
enzyme
Further,
own 70S
both
activity
this may
with
not
How-
contamination
template.
polymerase,
obtain
from
endogenous
“cellular”
as
cells.
appear
was
the
found
virus
report
then
efforts
virus
RDDP
that
are
For example,
column
at
properties
origin
just
C-type
any
to the reaction
mixture.
from
RSV prefers
its
purification
have
identity
differences.
al.’6 on
suggests
that
other
sources.42
With
human
tumor
cells
previously
having
705 RNA from a proven
the
cellular
enzyme
preparations
are,
We
these
to
ENZYME?
of leukemic
different
particles
than
from
and
VIRUS
for
enzymes
for
in- comparison
to solubilize
RNA,
criteria
and
account
in
rA.dT
did
i.e.,
THE
AS
enzyme
until
mammalian
is considerably
70S
the
variable
might
from
the
the
SAME
The
meaningful
since
or virus
that
by
settled.
from
recent
report
of Schlom
isolated
from
human
two-fold
THE
previously,
the fine biochemical
may
differ
from
those
of animal
of the
erase.9
can use
not
purified,
other
They
is not
different
may
more,
RNA
CELLS
to find certain
points
of dissimilarity.
RLV
elutes
from
a phosphocellulose
slightly
cells
avian.
The
like particles
question
It is easy
from
concentration
properties
NEOPLASTIC
certain
partially
Since
RNase
that
a
above,
certain
of utilizing
a
and
Gallo,
R.,
in
oligodeoxynucleotide
is
has not been
ruled
out.
that if the DNA
fragment
as the template,
as shown
below.
_____________________
RNA
DNA
The
fragment
reaction
primer
template.
On
.0K
may then
proceed
that
is hybridized
the
other
hand,
building
to the
according
end
off the 3’-OH
group
of the DNA
RNA,
while
the RNA
acts as the
to Spiegelman
( personal
communica-
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
126
ROBERT
)
tions
the
purified
RNA.
a
This,
enzyme
of
the
a
sure
If
critical
There
of
cellular
ha’e
of
three
different
that
three
RDDP
(Yang,
and
not
rifampicin
the
DNA
In
with
cells
derived
to
comparison
on
can
an
he said
enzyme
not
\Ve
but
been
are
Callo,
course
only
RNA
by
in
tile
depends
with
the
has
ranges
potent
of
the
efficacy
been
has
extracts
whether
established
IN
extended,
that
that
this
activity
and
must
COfll)aring
and 1)hysical
from RLV,
1)roI)(rties
of each
normal
lymphocytes
established
) , leukemic
lymphoblasts,
the
of
by
virus
the
several
stressed
RDDP
viral
also
cellu-
and
templates,
Scolnick
CE1Ls
illhibitor
et
IDENTICAL
in template
some
at
will
the
eviabove
al.41
TO
ThosE
for
leukemic
tissue
culture
CELI.s?
noted.4#{176} On
donors
of
between
NoRIA1.
LEUKEMIC
differences
been
normal
inhibitors
Similarity
not
some
and not
i.e., to
viruses
are
same
preparation;
which
tumor
data
these
structural
degree
templates,
If these
poly-
)
AM\T
concentration
from
associ-
the
and
R.,
pol’-
his
the
argument
by complexing
acid
RDDP
cells.
DESCRIBED
have
)resefltly
same
certain
coli.43’44
he
columns,
with
certainty
activity(
s)
dT.rA,al44l
has
crude
from
the
E.
the
and
nucleic
and
a common
to
act
derivaDNA
inhibit
possess
elute
molecular
rifampicmn
FeLV,
C.,
Of
within
leukemic
POLYMERASES
cells
the
only
appear
from
mobility
relatively
Smith,
Apparently,
e.g.,
that
normal
inhibited
F.,
OF
and
must
RNA-DNA
similar
derivatives
( MSV,
viruses
utilize
( AT ) ; ( 3 )
d
certain
and
can
prefer
poly
suggesting
rifampicin
RDDP
(1)
some
DNA-dependent
itself.’32’4
Green
viruses
is
virion
both
with
by
celluand
other
DNA
polymerases,
then
it would
be additional
hetw’een
cellular
and viral enzymes,
since
as stated
of
by
ARE
well
extent
tumor
tumor
inhibit
enzyme
enzymes,
certain
from
cells
Herrera,
polymerases,
tile
and
volume,4’
interacting
similarity
effects,
same
RNA
roven.
derivatives
illilii)it
the
communication
).
rifampicin
derivatives
by
a number
for
very
DNA
However,
RDDP:
but
work
RNA
derivatives
DNA
illclu(ie
lar
S.,
viral
a
information
flow
( see below).
theory
and
a similar
require
between
(2 )
since
of
C.,
personal
that
these
adequately
dence
leukemic
to
different
species
The
enzyme
other
inhibited
argued
inerase
protovirus
similarities
ribohomopolymers
in
of
to
viral
a contaminating
does
distinct.
reversal
RNA
Purified
supply
RDDP
mechanistically
for
highly
a
not
cellular
Temin’s
human
with
done
does
and
striking
dT.rA;
are
l)e
vhicli
has minimal
effects
on
are not inhibited
by rifampicin
and
been
of
columns
(4 )
and
Todaro,
on proof
case
some
poly
as
tives,’2414t
merases
to
can work
with
single-stranded
any DNA
fragment
hybridized
preparation
the
Both
filtration
feature.
derivatives
is
synthetic
gel
ates4
enzyme
enzyme.
such
sizes;
the
this
course,
double-stranded
from
have
cOml)onent
are,
hybrids
would
viruses
remove
enzymes
will obviously
he
still will have
implications
RDDP
remain
tumor
should
that
course,
fragment.
I)rinler,
the
of RNA
manner
to be
DNA
lar
RDDP
in
C. GALLO
the
preferences
other
hand,
similarities
least
normal
utilize
the
is identical
await
template
to RDDP
described.4’
cells
It
do contain
strand
of
of leukemic
cells
purification.
specificities,
E. coli.
been
proliferating
rihohomopolymer
further
DNA
polymerase
( fresh ) , “normal”
and
have
with
effects,
of
isolated
an(1 partially
lymphoblasts
( tissue
As
noted
above
with
inhibitors,
purified
culture
the
leu-
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DNAPOLYMERASE
127
( ALL )
kemic
RDDP,
a single-stranded
of the
RNA
C.,
murine
mouse
mammary
not
the
is now
tumor
RDDP
may
human
tumor
be
isolated
et al.20’21
by
now
as
great
Visna
The
and
his
CLINICAL
discovery
the
RNA
if RDDP
DNA
hybrids
tracts
and
cells.
with
human
against
with
the
the
a
type
C-type
B
virus
of
APPROAChES
of RDDP
polyirierases
of
polymerase
has
tumor
viruses
other
in
sufficient
be
in plasma
possible
( Talal
N.,
from
by
lupus
and
may
not be specific
the RDDP
of
from
normal
cells
not
do
show
cells
RDDP
does
Another
approach
cells,
that contains
activity
which
of
R.,
tumors.
This
quantity
then
is to
an
is activated
may
)
be
transformed
A second
.
done
in
the
these
The
sera
of
hybrid
approach
very
near
RNA-
in cell
will
future
exlatter
patients
structures
be
make
DNA
and then
to
to look for complimentary
in the
for
For
cells,
products
approaches.
against
virus
to
experiments
in the search
of this activity.
these
present
directed
tumor
in
for
immunologic
antibodies
in preparation
RNA
hybridization
approaches
the assay
just
looking
and
use
other
than
are
We
biochemical
the
Gallo,
human
up
erythematosus
a human
111 molecular
opened
detected.
through
systemic
in various
antibodies
human
prepared
now
and
polymerases
RDDP
is present
may
RDDP
DNA
and
Virus
presence
DNA
DNA
the
cross-reactions
findings
with
possible
AND
Tumor
DNA
sensitive,
of
of
he
virus,
from
antibodies
be
colleagues15-”
the assays
for
nonviral
cellular
If
are
may
RDDP
negative
positive
APPLICATIONS
RNA
of
The
that
needed
Moore
RNAase
example,
may
anti-
detergents.
“footprints”
with
of
directed
Foamy
is whether
inhibit
activity
with
tumor
virus
705 RNA
and the ieukemic
might
be a criterion
for viral origin
of the enzyme.
find a particulate
fraction,
in tumor
but not in normal
nonionic
the
( Todaro,
al.45
antibodies
virus,
interest
will
are
this
viruses.
endogenous
with
but also inhibit
tile RDDP
virus,
and feline
sarcoma
this
by
copy
found
et
that
foulld
leukemia
in progress.
viruses
indicate
\Vhat
“Footprint”
tumor
vitIl
if a true
cross-reactivity
Aaronson
AMV,
RDDP
and
As described
above,
enough
to distinguish
RNA
for
RDDP,
feline
RDDP,
POSSIBLE
Usefulness
test
recently
from
virus
found.
virus
to
RLV
of immediate
are
oncogenic
not
synthesis
virus.
that
experiments
of some
ery
RDDP
animal
These
RDDP
particle
Priori
inhibit
tumor
A question
have
be
polymerases.
not ollly inhibit
tumor
viruses,
RNA
do
but
will
purified
)
of RLV
virus,
against
tIleSC
conlnulnication
RDDP
of other
approach
against
PerSoIlal
recently
succeeded
in obtaining
l)NA
human
rRNA.
\Ve do not yet know
but so far this reaction
has not been
lynl)hocytes.
fronl
nornlal
and
iml)ortant
prepared
against
285
is synthesized,
I)Olynlerases
Another
bodies
we
RNA,
to
use
use
this
RNA
in view
of
the possibilities
that the C-type
virus20
of Priori
et al. and the viruslike
partides
from
human
milk
isolated
by Moore
and his associates15
may
represent
human
RNA
tumor
viruses.
Finally,
antibodies
may be prepared
against
human
with
isolated
virus
RDDP.
The antibodies
could
human
tumor
cells
by determining
from
these
cells.
then
be used in cross-reactivity
if it inhibits
a specific
studies
polymerase
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128
ROBERT
Diagnostic
a iid Prognostic
( Tse
The
observation
DNA
polymerase
macic
activity
invariably
higher
niucll
normal
letikocytes,
activity
rapi(ily
interesting
utility.24
This
activity
and
to
see
in
biochemical
if tiliS
sensitive
approach
for
if, in fact,
tilis
index
well
Therapeutic
Concepts:
The
polymerase
may
distinguish
DNA
OIlS
cells,
selective
)olymerase
of RDDP
of
will
neoplastic
be useful
e.g.,
the
of
destruction
of
a ilurnan
effect
110
cells.
cell
state.
into
cells.
reniission,
cells
with
a cell
Oil
( including
activity
neoplastic
that
sometimes
nuclease
be
mature
of interest
assay
not
information
results
be difficult
to determine
relapse
occur
but
some
then
resulting
that
survive
in
for
without
blasts
are
any
found
detail
and
of
concept
signs
evidence
was
later
was
recently
transplanted
leukenlic
into
cells
were
provided
an
by
untreated
found
in
Fialkow
female
abundance,
last
be
now
true
see
disease,
in
cvi-
and
It is reason-
Male
the
blast
neoplastic
may
of their
acute
the
put
readily
leukemic
‘We
et al.4t
and
may
genome
of
in abundance.
with
if RDDP
activity
believethat
in these
patients
the inciting
agent
may
still
in subsequent
neoplastic
trallsfOrmation.
This
argument
in the incidence
of new
clones
of transformed
cells with
between
relapse.
Cytogenetic
analyses
have
already
been
that
suggests
that this may be the case
( Fig. 1 ) . Additional
dramatic
below.
Theoretically,
the
explanation.
for
in selective
are
to kill
lleO-
selective
maintenance
leukemia
held
A
of viral
real)l)earance
full
for
of this
is, expression
widely
is the
years
leukemic
in
of a failure
This
this
is discussed
inhibition
the
is necessary
result
acute
not
inhibitor
(3 )
nay
necessary
with
because
agents?
patients
then
be
or
A selective
is necessary
in Leukemia?:
an RNA
virus
That
not
of
inhibitors
whether
)
inhihitioll
Relapses
involves
iatients
occurs
I doubt
possible,
the neoplasia.
e.g., if RDDP
of
in origin,
may
solely
suddenly
be
virus.
(2
if this
activity
transformed.
)
investigation
Selective
another,
and if qualitative
or even
DNA
polymerases
of normal
and
consideration
nially
the
(1 )
a
for Some
leukemia
is viral
for
able
to
resulting
increase
weeks
the
effort.
important,
A fourth
chemotherapeutic
instances,
deuce
marrow
to
to
these
factors.
may
state,
already
RDDP
However,
but
relapse
Does
then
CML
led
lower
it will
laboratory
from
clinically
Responsible
of human
leukemic
several
maintellallce
he
transformed
these
is “Reinfection”
if the pathogenesis
our
cells
is from
in determining
may
tile
in
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polymerase
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and/or
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intervals
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comparing
with
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compared
and
enough
chemotherapy
transformation
inilihitor
most
and
other,
examinations,
worth
is based
differences
neoplastic
have
and
rationale
illhibitOrs
quantitative
plastic
naturally
blasts
By
that
diagnostic
morphology,
tilan
compared
Approaches
General
DNA
and
as some
useful.
is useful
cells
in leukeniic
is clinically
approach
leukemic
leukocytes,
cllemQthera)y,24-4
nlight
have
( as
approach
kinase
thymidine
of
normal
the standard
hematologic
ulorphologic
clinical
laboratories
to rapidly
accumulate
\Vitil
in
extracts
following
these
assays
that
be a more
crude
his associates
that
the
ratio
of
(rA.dT)
to DNA
(dC.dG)
was
and
hybrid
proliferating
(IilllilliSiled
higher
) might
cells
by Spiegelman
with a DNA
even
roiosa1
C. GALLO
be
predicts
an
increasing
reported
in
and more
sibling
leukemia.
cells
present
were
bone
Ten
male
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DNA
POLYMERASE
129
$00
-
Fig.
of
1.-Incidence
changes
in
karvotype
0
of
80
,,
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leukemic
blast
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relapses.
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patients
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were
0
These
findings
)Olymerase
liberating
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potent
lymerase
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mutants
in
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interactions
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in
with
interest
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methyl
benzyl
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RNA
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theoretically
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rifampicin
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)
DEATH
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NEOPLASTIC
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ANY CARCINOGEN
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DNA OR RNA WITH INFORMATION
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as
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if,
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human
N-demethylrifampicin
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is involved
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agent
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all
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Fig.
J. Whang-Peng,
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retransformation.
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L
66
42
54
TIME OF SURVIVAL
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From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
130
ROBERT
OH
CH3O
CH3
OH
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,
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et al.45 recently
inilibit
the
that
derivative
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enzymes
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derivatives
greater
another
benzyl
one
same
with
it is conceivable
alld
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( unpublished
selectivity
to
rifampicin
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to
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it interferes
it does
200
due
tile
compounds
because
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ulade
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also been
daunomvcin
be
important
The
effect
studied.
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are inhibitors
to determine
of some
other
instance,
ethidium
( Hirschnlan,
S.,
the
mechanism
cohllpOUll(lS
On
RDDP
activity
bromide
1)ersOllal
and,
to a lesser
comnlunications
of action
and
the
specificity
have
degree,
) . It will
of in-
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
DNAPOLYMERASE
hibition
131
in each
selectivity
For
This
appears
since
they
of
may
the
compete
RNA-DIRECTED
that
involve
recently
more
reported
formed
cells.
the
The
following
RNA+
tumor
the
case,
be
same
pathway
could
Bishop
longer
instance,
SECOND
into
pathway
may
RNA-directed
exist
RNA
species
capable
scriptase
RNA
agents
another
RNA
that
of
the
than
of
of
by
described
polymerases,
tumor
chelating
RNA
may
RDDP
transforming
mutant
OF
defective
inactive
defective
“active”
RNA
a therapeutic
PATHWAY
for RNA
virus
for
TUMoR
VIRUSES?
of RNA
Green
)
-
account
tile
agent.
in
tumor
et al.5#{176}
MSV-trans-
for
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by:
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pathway
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of antiviral
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all
of
cells,
also
be
to this
+
and
RNA
involved
RNA
viral
animal
in viral
is
an
-
RNA
in transcription
tumor
viruses
be that the
transformation,
of polymerase
genome
genome
An alternate
RNA
, i.e.,
RNA
polymerase
-
and in nontumor
playing
a role
cells.
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in neoplastic
type
the
of the
pathway.
direct
conversion
of RNA
However,
an RNA-dependent
in normal
bind
5%
DNA.
Perhaps
not
the reverse
transcriptase
the enzyme
from
pathway
involved
replication.
should
could
If so,
be
be
reverse
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looked
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for
as
compounds.
IMPLICATIONS
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use
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transcriptase
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viruses,
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scheme:
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pathway
Levinson
for
taken
SYNTHESIS:
RNA
The
virus
with RDDP
from
an
in effect
acting
like
virus,
RNA
is possible
viruses
by
i)e
likely
virion
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nligllt
active
approach
niutation
RNA
to
will
to the
templates.
therapeutic
a
Advantage
RNA
inhibitors
specifically
acid
in a defective
Hanafusa.27
It
nucleic
example,
result
important
binding
interesting
viruses.
cells.
by
with
Another
The
work
by interacting
may
case.
and
OF
Cell
RDDP
OTHER
THAN
IN
NEOPLASIA
Differentiation
The
ability
of virion
RDDP
to catalyze
to virus
705 RNA
immediately
raises
the
serve
as templates
for this enzyme
of other
before,
we have
shown
that
some
cellular
synthesis
of DNA
complementary
question
whether
other
RNAs
may
cellular
polymerases.
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cytoplasmic
RNAs
may
serve
as
templates
as
Smith,
RNA)
for
cellular
G., and Gallo,
were
reported
RDDP3215
as
well
R., unpublished
results
almost
simultaneously
certain
)
.
phage
RNAs
Similar
results
by Cavalieri
( with
with
( Sarin,
P.,
cytoplasmic
E. coli DNA
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
132
ROBERT
)Olymerase,
may
and
function
tenlplates
by Bosmann.17
have shown
Ported
RDDP
complementarity
It
is
f)OsSihle
synthesis
it
clear
is
small
only
DNA
of
to
cellular
a tool
will
that
showing
in mOuse
portions
complementary
theoretically
tilat
findings
RDDP
for
It silOuldi
be noted
that
activity
with cellular
RNA
been
denlonstrated
between
that
of
similar
subsequent
as
cytoplasmic
cells have
leukemic
although
templates,
the
the
the reports
in 110 case
RNA
and
RNA
RNA
are
the
on
as
cellular
yet
product
has
DNA.
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if
be achieved,
synthesis
of specific
can
rapid
for
RNAs
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re-
copied.
templates
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C. GALLO
genes.
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a different
dence
lie
for
has
place
namely
approach,
cytoplasniic
that
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to
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oocytes
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reasonable
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as suggested
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direct
vivo
III
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the
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idea
tilat
( see
last
)
as
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.
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RNA
dinlethyl
benzyl
essential
theory
activity
described
above,
templates
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derivative
genes
develops
cells.
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the
inhibitor
is specific
of
( at
are
plays
a
key
and
and
biology
RDDP
that
in
)
role
in
it may
in the
utilize
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amplification
minimum
is no
hypothesis
respects,
gene
for
above,
there
Protovirils
is testable
in sonic
any previous
proposal
the reports
of cellular
a
authors
important
and
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inhibition
the
laboratories,
is
it
from
as noted
extremely
cells
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inhibitor,
results
as
et al.0#{176}
However,
normal
rifampicin
RDDP
rRNA
as
the
of
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takes
these
although
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under
test in many
it at present.
in
an
suggestive
cellular
normally
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that
Green
component
research
as
premise
is operative
an
attractive
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decade.
cellular
to stlp)Ort
is
below
Therefore,
by
rifampicin.
of
of
presently
RDDP
a
the
n
for
which
is blocked
of
findings
case.
OflC
cytodifferentiation
stimulate
the
reported
as templates
for rRNA,
in embryonic
is based
by
be
Ilot
acting
of genes
amplification
nlecllanislll
1loted,’
tile
that
speculate
has
)
Xenopus,
of
derivative
benzyl
transcriptase
attractive
( rRNA
amplification
111 (lifferentiating
tile
Tocchini-ValentinF’
RNAs
in keeping
the
with
hypothesis.
inforniation
Transfer
Another
critical
differentiation
)
ticularly
for
of
RD1)P
of the
RNA2.O:l
that
Antibody
It
the
or
RNAs
the
of
up
there
function
cell
one
which
is no
are
reports
as yet no one
actually
( in
hypothesis
from
complexes,
Although
cells,
there
However,
taken
protovirus
information
RNA-protein
cell.
accepting
regard
to cell
to another,
parwill be templates
evidence
of uptake
has reported
in the
for
of
uptake
of
crude
conclusive
whole
cvi-
explain
some
cell.
Production
is a)parent
that
a reverse
aspects
of the secondary
of a specific
new species
ate
antibody
then
i)155
these
of
trallsfer
1)>’ mammalian
aild
of tRNA.a4
111RNA
dleflCe
coniponent
involves
RNA
species
cells
is syntllesized.
to
other
) or
cells
amplify
tranScril)tase
immune
of RNA
Tile
and insert
genomes
mechanism
After
induction
of the transcription
antigenic
stimulation,
the appropri-
response.
following
RNA
or
a ribonucleoprotein
( perhaps
information
for
this
might
species
of
complex
previously
RNA
through
may
lacking
in
an RDDP.
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
DNAPOLYMERASE
The
133
transcription
of
RECENT
Two
THEORIES
The
main
since
tam
tile
tenets
This
vitii
tile
to
TUMOR
a second
VIIWsEs
unorthodox
for
but
least
or
roles
for
of
this
information
RNA
tumor
virus
noted
OIl
111
tinder
iy
the
none
of
opposedi
theory.
(1)
normal
embryonic
thought
Cell
vertebrates
a
presumably
and
( e.g.,
cells
)
cells.
lead
to
early
Exposure
( such
itself
epigenetic
OI1C
)
viruses
as DNA
determine
if
derepression
Oil
theory,
mechanism
Mans’
sPecific
nay
for
factors
IllIhly
fulldamentally
controls
for
usually
but
C-type
stable
a
of
Protovirus
virus
chemical
C-type
ilave
altera-
at
same
stage
are
than
dlldi
be
unique
(5 )
reactivated.
antigens
radiatioll-induced
of
viruseS.
RNA
species
to
neoplasia)
or
tile
indicating
repressedi
Several
studies
C
many
DNA
development,
genomes
ailtigens
tissues
as it naturally
proteins
of
that
ill
mammals,
to
trallsformation
group-specific
or
that
the
virus-producing
rather
thought
with
conditions
shown
present
of
oncogene
certain
to ty)e-C
have
Cancer
tile
in keeping
under
are
revealed
for
all
that
particles
illitially
tissues
life
viruses
(3 )
neoplastic
in fetal
active
silOvn
trailsfOrnl
tilillOr
( sometimes
evidence
are
studies
with
in fetal
process
RNA
with
RNA
studies
I)resellt
the
have
embryogenesis.
cells
are
they
spontaneously
generally
tunior
below
Seroepidemiologic
biochemical
iii
listed
possibilities,
experiments
(2 )
is associated
in
ilave
particles
adult
shown
themselves
neoplasia.
IIy)ot/lesis
Temin’s
somatic
is an
switcil
findings
culture
ill early
occurs,
appear
oncogene
alternate
cells
to be
tissues
ioth,
from
includes
and dle)eIlding
develop.
control,
regulatory
the
to
cells.
neoplastic
in
a
i.e.,
RNA
virogene
genotype
will
coIl-
C-type
genotype.
as
present
the
that
This
tumor
host
the
or
of
Proliferative
Activation
neoplasia,
Temin,55
idlea
occur.
all
transmitted,
other
and
repressor
productioii,
Although
theory
vill
or
( nonproliferative
perhaps
)
vertebrates
( oncogene
mature
Todaro51
all,
Cd’11.
in undifferentiated
viruses
genome
normally
whether
)
is vertically
and
Huebner
if not
portions
transformation
and
other
)
by
many,
to dlaugllter
in adult
irradiation,
viruses
activation
neoplastic
in part
that
producing
cell
from
normally
not
carcinogens,
tumor
for
and
proposed
are
( “virogene”
next
( at
)
origmally
Huebner,-T
information
is expressed
embryo
As
RNA
INVOLVING
oncogenesis
idea,
this
by
responsible
tilat
subsequent
I)rOI)osedl.
information
to
portion
imaginative
cell
inlplications
anism
of
genetic
generation
based
of
i)een
extended
viruses.
that
occur
Theory
and
(4 )
then
ONCOGENESIS
theories
recently
Oncogene
are
OF
iilterestillg
have
viruses
tioll
‘ill
challenge.
antigenic
to
genomes
these
genotypic
to
for
cell
secondary
theory
variatiOll
differentiation
antibody
proposes,
alld
among
gene
other
things,
and
growth,
response,
the
as vell
origins
a mechanism
with
amplification
as
of
their
providing
RNA
for
inherent
a
leukemia
mech-
and
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
ROBERT
134
sarcoma
viruses,
theory
the origin
at least
include
and neoplastic
transformation.
In common
of the C particles
are from cellular
genes,
“protovirus.”
The
latter
arise
as products
template
oncogenesis
merases
Altered
could
occur
the carcinogen
and
RDDP.
or
abnormally
from
changes
would
do this
( this
)
How
.
with
tile oncogene
portions
of which
of a cellular
RNA
integrated
protoviruses
lead
to
in RNA,
DNA,
or the
polyis not answered
by the theory,
and, of course,
neither
of production
of the
The
observations
this nor the oncogene
theory
accounts
for the
cancer
from
the altered
DNA.
( listed above ) in keeping
with
the oncogene
all
the
compatible
Temin’s
regulatory
and
with
combines
mechanisms;
be present
cells;
( 3 ) requires
Since
the theory
been
described
theory.
(1 )
proposal
switch
it must
protovirus
viral
in at least
the
some
its
originator,58’80
a novel
approach
opens
cells
the
than
rather
theory
is
RDDP
embryonic
RNA.
and
it has
accoullt
here
very
recently
is not
needed.
of great
importance
of the unusual
moments
every
in
are
theory
particularly
presumably
evaluation
already
one
theory
ideas
to
and
mechanism
oncogene
mutation
key
a vigorous
avenues
to the
somatic
central
transfer
of information,
is too new for detailed
by
contrast
normal
Suffice
it to say that some aspects
are
and in its total content
it may represent
when
In
and
(2 )
C. GALLO
sphere
in neoplasia,
in biology
of biology.
CONCLUSIONS
The presence
has been
found
of some
mutant
of an RNA-dependent
DNA polymerase
or reverse
transcriptase
in every
RNA oncogenic
virus
investigated,
with the exception
viruses
that have
lost the ability
to infect
or transform
normal
cells. It is assumed
that the role of the
a DNA
copy,
allowing
the viral genome
Nononcogenic
dependent
have
been
this
type
an
may
RNA
and
over
whether
reverse
i.e.,
n
shown
the
isolated
potential
practical
and it has already
has
any
DNA
great
the
enzyme
of this
in a human
from
an
RNAwhich
there
from
human
care
reverse
notion
Since
or
With
of a true
the
tissues
that
to avoid
transcriptase
that
the
is sometimes
particle
serious
are
is
con-
viruses,
of this
molecular
to this situation.
adapted
in any
normal
tumor
tissue
RNA
affinity
polymerase
does
not in itself
there
is no published
presence
an
usefulness
with
these
templates
present.
At this time
of its presence
that
information
activity
to
of the Foamy
viruses
However,
it is thought
oncogenic.
presence
been
viral 70S RNA
host cell DNA.
let
biological
reverse
transcriptase
( catalyzing
synthesis
of DNA
natural
RNAs)
in cells
is more
difficult
to establish.
templates
such
as the
RNA-DNA
hybrids
poly
of reverse
transcriptase
has led to some confusion.
transcriptase
virtually
to be
support
oncogenic.
particles
polymerase
exception
transcriptase.
strongly
potentially
The presence
of a true
from
pure single
stranded
The
use of some
synthetic
rA.dT
to detect
the presence
Although
be
would
alone
oncogenic,
the
approach
is obvious,
s’pecificity,
the
demonstrating
particle
virus
troversy
contain
with
reverse
eventually
of pitfalls,
isolated
either
polymerase
to contain
of virus
a number
in an
viruses
RNA
shown
enzyme
is to convert
to be inserted
into
oncogenic
indicate
definitive
cell.
would,
virus
for
these
will
use
that
templates
them.
reverse
Thus,
transcriptase
information
may
be
is
demonstrating
An unequivocal
therefore,
they
lack
activity
demonstration
appear
present.
to
indicate
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
DNA
POLYMERASE
135
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1972 39: 117-137
Analytical Review: RNA-Dependent DNA Polymerase in Viruses and Cells:
Views on the Current State
ROBERT C. GALLO
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