Lewin Benjamin (ed.) Genes IX
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.
Phage
and bacterial DNAs align Staggered cleavages
lead
to crosswise
pairing
G CTTTTTTATACTAA
C G AAAAAATATG ATT
Bacterial DNA
Recombinant
junctions
are sealed
to
generate
integrated
prophage
DNA
Phage DNA
q3;i,Jli=
i.ii,::S Staggered cteavages
in the common
core sequence
of attP
and
attB
a[[ow
cross-
wise reunion to
generate
reci
procaI
recom bi nant
junctions.
Integrases
use a mechanism similar
to that of
type I topoisomerases,
in which a break
is made
in one DNA strand
at a time. The difference
is
that a
recombinase
reconnects the ends cross-
wise, whereas
a topoisomerase
makes a break,
manipulates
the ends,
and then rejoins the orig-
inal ends.
The basic
principle
of the
system
is
that
four molecules of
the recombinase
are
required, one
to cut each of the
four strands of
the
two duplexes
that are recombining.
iltl:*ft|
.1-'-.:.;r-il
shows the
nature of the
reac-
tion
catalyzed by
an integrase.
The enzyme
is
a monomeric
protein
that
has an active site
capable
of cutting
and ligating DNA.
The reac-
tion
involves an attack by
a tyrosine on
a
phos-
phodiester bond. The 3'end of
the DNA chain
is linked
through a
phosphodiester
bond
to a
tyrosine
in the enzyme.
This releases a
free 5'
hydroxyl end.
TWo enzyme units
are bound to each
of the
recombination
sites.
At each site, only
one of
the units attacks
the DNA.
The symmetry of
the
system
ensures that
complementary
strands are
broken
in each recombination
site.
The free
5'-OH
end in each
site attacks the
3'-phospho-
tyrosine
link
in the other site.
This
generates
a
Holliday
junction.
The structure
is
resolved when the
other
two
enzyme
units
(which
had not been
involved
in the first cycle
of breakage
and
reunion)
act on
the
other
pair
of complemen-
tary
strands.
The successive
interactions
accomplish
a
conservative
strand
exchange,
in
which
there
are no deletions
or additions
of
nucleotides
at
the exchange
site,
and there
is no
need
for input
of energy.
The
transient
3'-phosphotyrosine
link
between
protein
and
DNA
conserves
the
energy
of the
cleaved
phosphodiester
bond.
f]:i;i-iilfl
i.1;.
]f.i
shows
the
reaction
intermedi-
ate,
based on
the
crystal
structure.
(Trapping
the intermediate
was
made
possible by
using
a
"suicide
substrate,"
which consists
of a synthetic
DNA duplex
with
a missing
phosphodiester
bond,
so that
the
attack
by
the enzyme
does
not
generate
a
free 5'-OH
end.)
The structure
of
the
Cre-/oxcomplex
shows
two
Cre
molecules,
each
of which
is bound
to
a I5
bp
length
of
DNA.
The
DNA is bent
by
-
1 00' at
the
center
of sym-
metry.
TWo of
these
complexes
assemble
in
an
antiparallel
way
to
form
a
tetrameric
protein
structure
bound
to
two
synapsed
DNA
mole-
cules.
Strand
exchange
takes
place in a central
cavity of
the
protein structure
that
contains
the
central
six bases
of the
crossover
region.
The tyrosine
that
is responsible
for cleaving
DNA in any
particular half
site
is
provided by
the
enzyme
subunit
that
is bound
to
that
half site.
This is called
czs
cleavage.
This
is true
also
for
the Int
integrase
and
XerD
recombinase.
The
1 9. 18 site-specifi
c
Recom
bi
nation
Resembles
Topoisomerase
Activity
TYr
5'
3',
J-5
tyr
2 Each
duplex
is
cleaved on
one strand
to
generate
a P-Tyr
bond
and
an
-OH
end
Tvr
5'
3'
j':'
-:a
-
*-
ql
"
OH
..*Tyr
3. Each
hydroxyl
attacks
the Tyr-phosphate
link
in
the
other
duplex
1.
Two
enzyme
subunits
bind to each
duplex DNA
4.
The reactions
are repeated
by the other
subunits
to
join
the
other
strands
i::{,i.ii'il
it.il*
Integrases
catalyze
recombination
by a mech-
anism
simi[ar
to topoisomerases.
Staggered
cuts are made
in
DNA
and
the 3'-phosphate
end is
covatentty
Linked
to a
tyrosine in
the
enzyme.
The free
hydroxyl. group
of
each
strand
then
attacks
the P-Tyr
tink
of the
other strand.
The
first
exchange
shown in
the figure
generates
a
HotLiday
struc-
ture. The
structure
is resolved
by repeating
the
process
with
the other
pair
of
strands.
FLP
recombinase
cleaves
i\
trans,
however,
which involves
a mechanism
in
which the
enzyme
subunit
that provides
the tyrosine
is
notlhe
subunit
bound to
that half
site,
but rather
is
one
of the
other
subunits.
@
Lambda
Recombination
0ccurs
in
an Intasome
r
Lambda
integration
takes
ptace
in
a [arge
comptex
that atso
inctudes
the
host
protein
IHF.
.
The
excision reaction
requires
Int and
Xis
and
recognizes
the
ends of
the
prophage
DNA
as
s
ubstrates.
Homotogous
and
Site-Specific
Recombination
fl$il&$
tr.ff.;t*
A
synapsed loxA recombination
comptex nas
a tetramer
of Cre recombinases,
with
one enzvme
monomer
bound
to each half
site. Two
of the four
active
sites
are
in
use,
acting on
comptementary
strands
ofthe
two DNA
sites.
Unlike the
Cre I lox recombination
system,
which
requires
only
the enzyme
and
the two
recom-
bining sites,
phage
lambda
recombination
occurs
in a large
structure
and
has different
compo-
nents
for each
direction
of the reaction (integra-
tion versus
excision).
A
host
protein
called
IHF
is required
for
both integration
and excision.
IHF
is
a 20 kD
protein
of two
different
subunits,
which are
coded
by the
genes
himA
and
himD.IHF
is
not
an essential protein
in E.
coli, and
is not
required
for
homologous
bacterial
recombination.
It is
one of
several
proteins
with the
ability
to
wrap
DNA
on a
surface. Mutations
inthe
him
genes
prevent
lambda
site-specific
recombination
and
can be
suppressed
by mutationsinl,int,
which
suggests
that IHF
and Int interact.
Site-specific
recombination
can
be
performe
d
in vitro
by Int
and IHF.
The in vitro
reaclion
requires
supercoiling
in
attP,
but not in
attB.
When the
reaction
is
per-
formed
in vitro
between
two
supercoiled
DNA
molecules,
almost
all
of the
supercoiling
is
retained
by the
products.
Thus
there
cannot
be
any
free intermediates
in
which
strand
rotation
could
occur. This
was one
of the
early hints
that
the
reaction proceeds
through
a Holliday
junc-
tion.
We now
know
that the
reaction proceeds
by the
mechanism
tlpical
of this
class
of enzy'rnes,
which
is related
to
the topoisomerase
I
mecha-
nism
(see
Section I9.18,
Site-Specific
Recombi-
nation
Resembles
Topoisomerase
Activity).
Int
has
two
different
modes
of binding.
The
C-terminal
domain
behaves
like
the
Cre
recombinase.
It
binds
to inverted
sites
at the
core
sequence, positioning
itself
to make
the
486
CHAPTER
19
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