Page 76 - Genetics_From_Genes_to_Genomes_6th_FULL_Part2

7.3 DNA Repair Mechanisms 235

Recall from Fig. 7.7 that if new DNA damage is re- Figure 7.16 Base excision repair removes damaged
paired before DNA replication occurs, no mutation be- bases. Glycosylase enzymes (light green oval) remove aberrant
comes established in the chromosomes. Cells have in fact bases [like uracil (red) formed by the deamination of cytosine],
evolved a variety of enzymatic systems that locate and re- leaving an AP site. AP endonuclease (purple oval) cuts the sugar-
phosphate backbone, creating a nick. Exonucleases extend the nick
pair damaged DNA and thereby dramatically minimize the into a gap, which is filled in with the correct information (dark green)
occurrence of mutations. The combination of these repair by DNA polymerase. DNA ligase reseals the corrected strand.
systems must be extremely efficient, because the rates of
spontaneous mutation observed for almost all genes are 1. Deaminated DNA with
uracil
very low.

Some DNA Base Damage
Can Be Reversed Uracil released
2. Glycosylase removes
Cells contain various enzyme systems that can reverse cer- uracil, leaving an AP
tain kinds of nucleotide alterations quickly and directly. For site.
example, if methyl or ethyl groups are mistakenly added to
guanine (as in Fig. 7.14b), alkyltransferase enzymes can
remove them so as to re-create the original base.
In a second example, the enzyme photolyase recog-
nizes the thymine dimers produced by exposure to ultravio- 3. AP endonuclease cuts
let light (review Fig. 7.8d) and reverses the damage by backbone to make a
splitting the chemical linkage between the thymines. Inter- nick at the AP site.
estingly, the photolyase enzyme works only in the presence
of visible light. In carrying out its DNA repair tasks, it as-
sociates with a small molecule called a chromophore that
absorbs light in the visible range of the spectrum; the en- 4. DNA exonucleases
zyme then uses the energy captured by the chromophore to remove nucleotides
split thymine dimers. Because it does not function in the near the nick, creating
a gap.
dark, the photolyase mechanism is called light repair,
or photorepair.

5. DNA polymerase
synthesizes new DNA
Damaged Bases Can Be Removed to fill in the gap.
and Replaced

Many repair systems use a general strategy of homology-
dependent repair in which they first remove a small region
from the DNA strand that contains the altered nucleotide, 6. DNA ligase seals the
nick.
and then use the other strand as a template to resynthesize
the region removed. This strategy makes use of one of the
great advantages of the double-helical structure: If one
strand sustains damage, cells can use complementary base
pairing with the undamaged strand to re-create the original (recall that uracil often results from the natural deamina-
sequence. tion of cytosine; review Fig. 7.8b). In this repair process,
after the enzyme uracil-DNA glycosylase has removed
uracil from its sugar, leaving an AP site, the enzyme AP
Base excision repair endonuclease makes a nick in the DNA backbone at the
In this type of homology-dependent repair mechanism, AP site. Other enzymes (known as DNA exonucleases) at-
enzymes called DNA glycosylases cleave an altered nitrog- tack the nick and remove nucleotides from their vicinity to
enous base from the sugar of its nucleotide, releasing the create a gap in the previously damaged strand. DNA poly-
base and creating an apurinic or apyrimidinic (AP) site in merase fills in the gap by copying the undamaged strand,
the DNA chain (Fig. 7.16). Different glycosylase enzymes restoring the original nucleotide in the process. Finally,
cleave specific damaged bases. Base excision repair is DNA ligase seals up the backbone of the newly repaired
particularly important in the removal of uracil from DNA DNA strand.