10.2: DNA repair
- Page ID
- 38247
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DNA replication is a highly accurate process, but mistakes can occasionally occur, such as a DNA polymerase (DNA pol) inserting a wrong base. Uncorrected mistakes may sometimes lead to serious consequences, such as cancer. Repair mechanisms correct the mistakes. In rare cases, mistakes are not corrected, leading to mutations; in other cases, repair enzymes are themselves mutated or defective.
Most of the mistakes during DNA replication are promptly corrected by the proofreading ability of DNA polymerase itself. In proofreading, the DNA pol reads the newly added base before adding the next one, so a correction can be made. The polymerase checks whether the newly added base has paired correctly with the base in the template strand. If it is the right base, the next nucleotide is added. If an incorrect base has been added, the enzyme makes a cut at the phosphodiester bond and releases the wrong nucleotide. This is performed by the 3′ exonuclease action of DNA pol. Once the incorrect nucleotide has been removed, it can be replaced by the correct one (figure 10.5(a)).
Mismatch repair
Errors not addressed during replication are repaired through the process of mismatch repair (figure 10.5(b)). Specific repair enzymes recognize the mispaired nucleotide and excise part of the strand that contains it; the excised region is then resynthesized — typically during S phase of the cell cycle — and the enzymes involved are those used for DNA replication. If the mismatch remains uncorrected, it may lead to more permanent damage when the mismatched DNA is replicated. Deficiencies in this repair process can result in Lynch syndrome, which is characteristic of nonpolyposis colorectal cancer.
In prokaryotes, the parental strand is determined by the methyl groups on adenine bases, while the newly synthesized strand lacks them. Thus, DNA polymerase is able to remove the wrongly incorporated bases from the newly synthesized, non-methylated strand.
In eukaryotes, the mechanism is not very well understood, but it is believed to involve recognition of unsealed nicks in the new strand, as well as a short-term continuing association of some of the replication proteins with the new daughter strand after replication has completed.
Errors during DNA replication are not the only reason why mutations arise in DNA. Mutations, variations in the nucleotide sequence of a genome, can also occur because of damage to DNA. Such mutations may be of two types: induced or spontaneous. Induced mutations are those that result from an exposure to chemicals, UV rays, X-rays, or some other environmental agent. Spontaneous mutations occur without any exposure to any environmental agent; they are a result of natural reactions taking place within the body.
Nucleotide excision repair (NER)
Another type of repair mechanism, nucleotide excision repair, is similar to mismatch repair, except that it is used to remove large, bulky damaged bases rather than mismatched ones. The repair enzymes replace abnormal, bulky, bases by making a cut on both the 3′ and 5′ ends of the damaged base. The segment of DNA is removed and replaced with the correctly paired nucleotides by the action of DNA pol. Once the bases are filled in, the remaining gap is sealed with a phosphodiester linkage catalyzed by DNA ligase (figure 10.5(c)).
This repair mechanism is often employed when UV exposure causes the formation of pyrimidine dimers (thymine dimers). When exposed to UV light, thymines lying next to each other can form thymine dimers. In normal cells, they are excised and replaced. Xeroderma pigmentosa is a condition in which thymine dimerization from exposure to UV light is not repaired.
Base excision repair (BER)
The process of base excision repair (BER) is similar to NER but tends to repair small modifications to individual bases, such as deamination of cytosine to produce uracil. In this process, the aberrant base is detected by a glycosylase that will cleave the N-glycosidic bond joining the base to the deoxyribose sugar. This leaves an apurinic or apyrimidinic site (sugar phosphate backbone lacking a base), which is cleaved by an exonuclease and repaired through a similar process as mentioned above (figure 10.6).
Double-stranded break repair
Double-stranded breaks are caused by ionizing radiation, such as X-rays or radioactive particles. This can be repaired through two processes: nonhomologous end-joining and homologous recombination. The major difference between these two processes is in nonhomologous end-joining there is direct ligation of the two ends without the need for a DNA template. This can result in some DNA being lost in the process. In contrast, homologous recombination requires a DNA template to repair the break. This allows for restoration of the duplex without a loss of nucleotides.
References and resources
Text
Clark, M. A. Biology, 2nd ed. Houston, TX: OpenStax College, Rice University, 2018, Chapter 14: DNA Structure and Function.
Karp, G., and J. G. Patton. Cell and Molecular Biology: Concepts and Experiments, 7th ed. Hoboken, NJ: John Wiley, 2013, Chapter 10: The Nature of the Gene and the Genome, Chapter 12: The Cell Nucleus and the Control of Gene Expression, Chapter 13: DNA Replication.
Le, T., and V. Bhushan. First Aid for the USMLE Step 1, 29th ed. New York: McGraw Hill Education, 2018, 34, 38–40.
Nussbaum, R. L., R. R. McInnes, H. F. Willard, A. Hamosh, and M. W. Thompson. Thompson & Thompson Genetics in Medicine, 8th ed. Philadelphia: Saunders/Elsevier, 2016, Chapter 2: The Introduction to the Human Genome.
Figures
Grey, Kindred, Figure 10.5 Comparison on three types of repair. a) Proofreading b) Mismatch and c) Nucleotide excision repair. 2021. CC BY 4.0.
Grey, Kindred, Figure 10.6 Summary of Base excision repair. This is a similar process to NER but requires a glycosylase. 2021. https://archive.org/details/10.6_20210926. CC BY-SA 4.0. Added DNA double helix grooves by Biochemlife. CC BY SA 4.0. From Wikimedia Commons.