Lewin Benjamin (ed.) Genes IX
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Some
of the
genes
for these
proteins
are mutated
in
patients
who
have
diseases due to deficien-
cies in DNA repair.
The
I(u heterodimer is
the sensor that
detects
DNA
damage by binding to the broken
ends. The crystal structure in
Ft{liltL
}i.:.i5 shows
why
it
binds
only to ends. The
bulk of
the
pro-
tein extends
for
about two turns along one face
of DNA
(lower).
but
a narrow
bridge between
the subunits,
located in the center of the struc-
ture, completely encircles
DNA. This means
that
the
heterodimer needs to slip onto a free end.
I(u can bring broken ends
together by bind-
ing
two
DNA molecules. The ability of
I(u het-
erodimers to associate with one
another suggests
that the reaction might take
place
as
illustrated
in iiiirlhli=
.".ii.i*.
This would
predict
that the
li-
gase
would act by
binding in the region between
the bridges
on the individual heterodimers.
Pre-
sumably I(u
must
change
its
structure
in order
to be
released from DNA.
Deficiency
in DNA repair
causes
several
human diseases.
The
common
feature is that
an
inability to repair double-strand breaks
in
DNA leads
to
chromosomal
instability. The insta-
bility
is revealed by chromosomal aberrations,
which are associated with an
increased rate of
mutation, which in turn leads to an
increased
susceptibility
to cancer in
patients
with the dis-
ease. The basic cause can be
mutation in
path-
ways
that control DNA repair or
in
the
genes
that code
for
enzymes of the
repair complexes.
The
phenotypes
can be very similar, as
in the
case of Ataxia telangiectasia
(AT),
which
is
caused
by failure of a cell cycle checkpoint
path-
way, and Nijmegan
breakage syndrome
(NBS),
which
is
caused
by a mutation of a repair
enzyme. One
of the lessons that we
learned
from characterizing
the repair
pathways
is that
they
are conserved
in mammals,
yeast,
and
bacteria.
The
recessive human disorder of Bloom's
syndrome
is caused by mutations
in a helicase
gene
(called
BLM)
that
is homologous to recQ
oI E coli.
The mutation results in an
increased
frequency of
chromosomal breaks and sister
chromatid exchanges.
BLM associates with other
repair
proteins
as
part
of
a large complex. One
of the
proteins
with which
it interacts is hMLHl,
a
mismatch-repair
protein
that is the human
homolog of bacterial mutL.The
yeast
homologs
of these
two
proteins,
Sgsl and
MLHI, also asso-
ciate,
identifying these
genes
as
parts
of
a well-
conserved
repair
pathway.
Nijmegan breakage
syndrome
results
from mutations
in a
gene
coding for a
protein
i:*li*:i:
.r:i-:"ij'+ Nonhomologous
end
joining
requires recog-
nition
of the
broken ends,
trimming
of overhanging
ends
and/or
filting, fotlowed
by tigation.
i:t{iLli.i{: J{.i,.ilii
The Ku70-Ku80
heterodimer
binds along
two turns of the
DNA doubte
hetix and
surrounds
the
helix
atthe center ofthe
binding
site.
Photos
courtesy
ofJonathan
Go[dberg,
MemoriaI
Sloan-
Ketteri
ng Cancer
Center.
20.1.2
A Common
System
Repairs
Doubte-Strand
Breaks
517
F:*il€i
!ri.l5
If two heterodimers
of
Ku
bind to DNA, the
distance
between
the two
bridqes
that encircte DNA is
-12
bp.
(variously
called
Nibrin
,
p95,
or NBS 1)
that is
a component
of the Mre I
I /Rad50 repair
com-
plex.
Its involvement
in repairing
double-
strand
breaks is
shown by
the formation
of
foci
containing
the
group
of
proteins
when human
cells
are irradiated
with
agents
that induce
double-strand
breaks. After
irradiation,
the
kinase
ATMP
(coded
by the ,4T
gene) phos-
phorylates
NBSl; this
activates
the complex,
which
localizes
at
sites of DNA
damage.
Sub-
sequent
steps involve
triggering
a
checkpoint
(a
mechanism
that
prevents
the
cell cycle from
proceeding
until
the damage
is repaired)
and
recruiting
other
proteins
that
are required
to
repair
the
damage
@
Summary
Bacteria
contain
systems
that maintain
the
integrity
of their
DNA
sequences in
the face
of
damage
or errors
of replication
and that distin-
guish
the DNA
from
sequences
of a foreign
source.
Repair
systems
can recognize
mispaired,
altered,
or
missing
bases in DNA,
as well
as other
structural
distortions
of
the double
helix. Exci-
sion
repair
systems
cleave
DNA
near a site
of
damage,
remove
one strand,
and
synthesize
a
new
sequence
to replace
the excised
material.
The
Uvr system
provides
the main
excision-
repair pathway
in
E. coli.
The
dam system
is
involved
in
correcting
mismatches generated
by incorporation
of incorrect
bases
during repli-
cation
and
functions
by
preferentially
remov-
ing
the
base
on the
strand
of DNA
that is not
methylated
atthe
dam target
sequence.
Eukary-
otic homologs
of the E.
coli
MrttSL
system are
involved
in
repairing
mismatches
that
result
from
replication
slippage;
mutations
in this
path-
way
are
common
in
certain types
of
cancer.
CHAPTER
20 Repair
Systems
Recombination-repair
systems
retrieve
information
from
a DNA
duplex and
use it to
repair
a sequence that has
been
damaged
on
both strands. The
RecBC
and RecF
pathways
both act
prior
to RecA,
whose
strand-transfer
function is involved
in all
bacterial recombina-
tion. A major
use of recombination-repair
may
be to recover
from the
situation
created
when
a replication
fork
stalls.
The
other capacity
of recA is
the ability
to
induce
the SOS response.
RecA
is activated
by
damaged DNA
in an unknown
manner.
It
trig-
gers
cleavage of the LexA
repressor protein,
thus releasing
repression
of many loci,
and
inducing
synthesis of the
enzymes
of both
exci-
sion
repair
and recombination-repair
pathways.
Genes under
LexA control
possess
an
operator
SOS
box. RecA also
directly activates
some repair
activities. Cleavage
of repressors
of lysogenic
phages
may induce
the
phages
to
enter the lytic
cycle.
Repair
systems can
be connected
with tran-
scription
in both
prokaryotes
and
eukaryotes.
Human
diseases
are caused
by mutations
in
genes
coding for
repair
activities
that are
asso-
ciated
with the transcription
factor
TFIIH.
They
have
homologs in
the RAD
genes
of
yeast,
which
suggests
that this repair
system
is widespread.
Nonhomologous
end-joining
(NHEJ)
is a
general
reaction
for repairing
broken
ends in
(eukaryotic)
DNA.
The I(u heterodimer
brings
the
broken ends
together so
they can
be ligated.
Several
human
diseases
are caused
by muta-
tions in
enzymes
of this
pathway.
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