section 24.6
DNA Mutation
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created by the thymine dimer. The combined action of
polymerase I and DNA ligase joins this inserted piece to
adjacent regions, thus filling in the gap. The gap formed in
the donor molecule is also repaired. If this exchange and
gap filling are done for each thymine dimer, two complete
single daughter strands can be formed, and each can serve
in the next round of replication as a template for synthesis
of normal DNA molecules. The system fails if two dimers
in opposite strands are very near one another because no
undamaged segments are available. Since recombinational
repair occurs after DNA replication, in contrast with exci-
sion repair, it is often called
postreplicational repair.
SOS Repair
SOS repair includes a bypass system that allows DNA
chain growth across damaged segments at the cost of fi-
delity of replication. It is an error-prone process; even
though intact DNA strands are formed, the strands are
often altered.
As described above, activation of the editing system
stalls replication at a thymine dimer. In SOS repair, the
editing system is relaxed to allow polymerization to pro-
ceed across a dimer. Relaxation of the editing system
means a loss of the ability to remove “incorrect” bases
added to the growing strand. Most of the time, pol III in-
serts two adenines at a dimer site. However, the distortion
increases the error frequency, allowing other nucleotides
to be added to the chain. This error-prone repair is the
major cause of UV-induced mutagenesis.
An important nuclear protein, conserved from yeast
to mammals, is the Ku
heterodimer.
This protein binds
to DNA and repairs double strand breaks caused by
x-rays and other agents. The Ku heterodimer is essential
in maintaining chromosome integrity.
Human Diseases and DNA Repair Deficiency
Human disease may result from inability to carry out cer-
tain stages of DNA repair. The best studied disease,
xero-
derma pigmentosum,
is a result of mutations in genes that
encode the UV excision system. Cells cultured from tis-
sue obtained from affected individuals are killed by much
smaller doses of UV light than are normal cells. Further-
more, the removal of thymine dimers in DNA from these
cells is very inefficient. People with this disease develop
skin lesions when exposed to sunlight and commonly
develop one of several kinds of skin cancer.
Ataxia telangiectasia
is characterized by severe abnor-
malities in various organ systems and a high incidence of
lymphoreticular cancer. Defective DNA repair was sus-
pected when patients developed an unexpected severe or
fatal reaction while undergoing radiotherapy for cancer.
As predicted, nontumor cells cultured from these patients
are hypersensitive to x-rays.
Fanconi’s syndrome,
a lethal aplastic anemia, is also
due to defective DNA repair. Cells from affected persons
cannot repair interstrand cross-links or damage induced
by x-rays. Two premature aging disorders (
Hutchinson-
Gilford syndrome
and
Bloom’s syndrome)
and several
other disorders
{Cockayne’s syndrome
and
retinoblas-
toma)
are also associated with defects in DNA repair. Cells
from patients with some chromosome abnormalities (e.g.,
Down syndrome) may also show aberrant DNA repair.
Several human DNA mismatch repair genes are as-
sociated with
hereditary nonpolyposis colon cancer
(HNPCC).
One of these mismatch repair genes (
hMSH2)
is located on the short arm of chromosome
2
; others are
located on chromosome 3. Defects in any of these DNA
repair genes predispose individuals to colon cancer as well
as to other cancers.
24.6 DNA Mutation
Mutation refers to any change in the base sequence of
DNA. The most common change is a substitution, addi-
tion, rearrangement, or deletion of one or more bases. A
mutation need not give rise to a mutant phenotype.
A
mutagen
is a physical agent or chemical reagent that
causes mutations. For example, nitrous acid reacts with
some DNA bases, changing their chemistry and hydrogen
bonding properties, and is a mutagen.
Mutagenesis
is the process of producing a mutation. If
it occurs in nature without the action of a known mutagen,
it is called
spontaneous mutagenesis
and the resulting mu-
tations are spontaneous mutations. If a mutagen is used,
the process is called
induced mutagenesis.
Types of Mutations
Mutations can be categorized in several ways. One system
is based on the nature of the change, specifically on the
number of bases changed. Thus, we distinguish a
point
mutation,
in which a single base pair is changed from a
multiple mutation, in which two or more base pairs differ
from the wild-type sequence. A point mutation may be a
base substitution,
a
base insertion,
or a
base deletion,
but
the term most frequently refers to a
base substitution.
A second system is based on the consequence of the
change in terms of the amino acid sequence that is af-
fected. For example, if there is an amino acid substitution,
the mutation is a
missense mutation.
If the substitution
produces a protein that is active at one temperature (typi-
cally 30°C) and inactive at a higher temperature (usually
