Читать книгу Cell Biology - Stephen R. Bolsover - Страница 103

If there were no way to correct altered DNA, the rate of mutation would be intolerable. DNA excision and DNA repair enzymes have evolved to detect and to repair altered DNA. The role of the repair enzymes is to cut out (excise) the damaged portion of DNA and then to repair the base sequence. Much of our knowledge of DNA repair has been derived from studies on E. coli, but the general principles apply to other organisms such as ourselves. Repair is possible because DNA comprises two complementary strands. If the repair mechanisms can identify which of the two strands is the damaged one, it can be repaired to be as good as new by rebuilding it so that is again complementary to the undamaged strand.

Two types of excision repair are described in this section: base excision repair and nucleotide excision repair. The common themes for each of these repair mechanisms are: (i) an enzyme recognizes the damaged DNA, (ii) the damaged portion is removed, (iii) DNA polymerase inserts the correct nucleotide(s) into position (according to the base sequence of the second DNA strand), and (iv) DNA ligase joins the newly repaired section to the remainder of the DNA strand.

Figure 4.5. Formation of a thymine dimer in DNA.

Base excision repair is needed to repair DNA that has lost a purine (depurination), or where a cytosine has been deaminated to uracil (U). Although uracil is a normal constituent of RNA, it does not form part of undamaged DNA and is recognized and removed by the repair enzyme uracil – DNA glycosidase (Figure 4.4). This leaves a gap in the DNA where the base had been attached to deoxyribose. There is no enzyme that can simply reattach a C into the vacant space on the sugar. Instead, an enzyme called AP endonuclease recognizes the gap and removes the sugar by breaking the phosphodiester bonds on either side (Figure 4.6). When DNA has been damaged by the loss of a purine (Figure 4.4), AP endonuclease also removes the sugar that has lost its base. The AP in the enzyme's name means apyrimidinic (without a pyrimidine) or apurinic (without a purine).

Figure 4.6. Base excision repair.

The repair process for reinserting a purine or a pyrimidine into DNA is now the same (Figure 4.6). DNA polymerase I replaces the appropriate deoxyribonucleotide into position. DNA ligase then seals the strand by catalyzing the reformation of a phosphodiester bond.

Nucleotide excision repair is required to correct a thymine dimer. The thymine dimer, together with some 30 surrounding nucleotides, is excised from the DNA. Repairing damage of this bulky type requires several proteins because the exposed, undamaged, DNA strand must be protected from nuclease attack while the damaged strand is repaired by the actions of DNA polymerase I and DNA ligase.

Even with all these protection systems in place, the cell divisions that create and repair our bodies generate errors, so that the adult human contains many cells with somatic mutations. Most are irrelevant to the specialized operation of that cell, or merely reduce its ability to function. Some, however, can cause cancer (page 241).