DNA Repair

DNA repair, any of several mechanisms by which a cell maintains the integrity of its genetic code. DNA repair ensures the survival of a species by enabling parental DNA to be inherited as faithfully as possible by offspring. It also preserves the health of an individual. Mutations in the genetic code can lead to cancer and other genetic diseases.

Successful DNA replication requires that the two purine bases, adenine (A) and guanine (G), pair with their pyrimidine counterparts, thymine (T) and cytosine (C). Different types of damage, however, can prevent correct base pairing, among them spontaneous mutations, replication errors, and chemical modification. Spontaneous mutations occur when DNA bases react with their environment, such as when water hydrolyzes a base and changes its structure, causing it to pair with an incorrect base. Replication errors are minimized when the DNA replication machinery “proofreads” its own synthesis, but sometimes mismatched base pairs escape proofreading. Chemical agents modify bases and interfere with DNA replication. Nitrosamines, which are found in products such as beer and pickled foods, can cause DNA alkylation (the addition of an alkyl group). Oxidizing agents and ionizing radiation create free radicals in the cell that oxidize bases, especially guanine. Ultraviolet (UV) rays can result in the production of damaging free radicals and can fuse adjacent pyrimidines, creating pyrimidine dimers that prevent DNA replication. Ionizing radiation and certain drugs, such as the chemotherapeutic agent bleomycin, can also block replication, by creating double-strand breaks in the DNA. (These agents can also create single-strand breaks, though this form of damage often is easier for cells to overcome.) Base analogs and intercalating agents can cause abnormal insertions and deletions in the sequence.

There are three types of repair mechanisms: direct reversal of the damage, excision repair, and postreplication repair. Direct reversal repair is specific to the damage. For example, in a process called photoreactivation, pyrimidine bases fused by UV light are separated by DNA photolyase (a light-driven enzyme). For direct reversal of alkylation events, a DNA methyltransferase or DNA glycosylase detects and removes the alkyl group. Excision repair can be specific or nonspecific. In base excision repair, DNA glycosylases specifically identify and remove the mismatched base. In nucleotide excision repair, the repair machinery recognizes a wide array of distortions in the double helix caused by mismatched bases; in this form of repair, the entire distorted region is excised. Postreplication repair occurs downstream of the lesion, because replication is blocked at the actual site of damage. In order for replication to occur, short segments of DNA called Okazaki fragments are synthesized. The gap left at the damaged site is filled in through recombination repair, which uses the sequence from an undamaged sister chromosome to repair the damaged one, or through error-prone repair, which uses the damaged strand as a sequence template. Error-prone repair tends to be inaccurate and subject to mutation.

Often when DNA is damaged, the cell chooses to replicate over the lesion instead of waiting for repair (translesion synthesis). Although this may lead to mutations, it is preferable to a complete halt in DNA replication, which leads to cell death. On the other hand, the importance of proper DNA repair is highlighted when repair fails. The oxidation of guanine by free radicals leads to G-T transversion, one of the most common mutations in human cancer.

Hereditary nonpolyposis colorectal cancer results from a mutation in the MSH2 and MLH1 proteins, which repair mismatches during replication. Xeroderma pigmentosum (XP) is another condition that results from failed DNA repair. Patients with XP are highly sensitive to light, exhibit premature skin aging, and are prone to malignant skin tumours because the XP proteins, many of which mediate nucleotide excision repair, can no longer function.