9.5: DNA Repair

We generally accept the notion that replication faithfully duplicates the genetic material, occasional making mistakes (mutating). At the same time, evolution would not be possible without mutation, and mutation is not possible without at least some adverse consequences. Because we see the results of mutation as disease, the word mutation in common parlance (and even among scientists) anticipates dire consequences. But mutations (changes in DNA sequence) are a fact of life. In fact, mutations occur frequently between generations. Most are inconsequential, and many are corrected by one or another mechanism of DNA repair.

9.5.1 Germline vs Somatic Mutations: A Balance Between Mutation and Evolution

Germline mutations are heritable. When present in one, but especially in both alleles of a gene, such mutations can result in genetic disease (e.g., Tay-Sachs disease, cystic fibrosis, hemophilia, and sickle cell anemia). Rather than causing disease, some germline mutations may increase the likelihood of becoming ill (e.g., mutations of the BRCA2 gene greatly increase a woman’s odds of getting 195, cancer). Somatic mutations in actively dividing cells might result in benign “cysts” or malignant tumors (i.e., cancer). Other somatic mutations may play a role in dementia (Alzheimer’s disease) or in some neuropathologies (e.g., along the autism spectrum). Since the complex chemistry of replication is subject to an inherently high rate of error, cells have evolved systems of DNA repair, so that they may survive high mutation rates. As we saw, DNA polymerases themselves can proofread, so incorrectly inserted bases can be quickly removed and replaced.

Beyond this, multiple mechanisms have evolved to repair mismatched base pairs and other kinds of damaged DNA that escape early detection. How often and where DNA damage occurs is random, as is which damage will be repaired and which will escape to become a mutation. For those suffering the awful consequences of unrepaired mutation, the balance between retained and repaired DNA damage is, to say the least, imperfect. However, evolution and the continuance of life itself rely on this balance.

9.5.2 What Causes DNA Damage?

The simplest damage to DNA is a point mutation, the accidental insertion of a “wrong” nucleotide into a growing DNA strand. Other mutations, equally accidental, include DNA deletions, insertions, duplications, inversions, and the like, any of which might escape repair. The causes of DNA damage can be chemical or physical and include spontaneous intracellular events (e.g., oxidative reactions) and environmental factors (e.g., radiation, exogenous chemicals).

These random events are in fact not rare, but frequent. Basing his calculations on studies of different kinds of DNA damage, Tomas Lindahl estimated that DNA-damaging events might be occurring at the rate of ten thousand per day! Lindahl realized that there must be some basic DNA repair mechanisms at work to protect cells against such a high rate of DNA damage. The discovery of the base excision repair mechanism earned Tomas Lindahl a share of the 2015 Nobel Prize in Chemistry.

Specific environmental factors that can damage DNA include UV light, X-rays, and other radiation, as well as chemicals (e.g., toxins, carcinogens, and even drugs). Both germline and somatic cells can be affected. While mutations can and do cause often debilitating diseases, it is instructive to keep the impact of mutations in perspective. Most mutations are in fact silent; they do not cause disease. And among mutations that could cause disease, much of the DNA damage is repaired. Cells correct more than 99.9% of mistaken base changes before they have a chance to become mutations. That is why we think of replication as a “faithful” process.

Let’s look at some common types of DNA damage that are usually repaired:

• Pyrimidine dimers: the dimerization of adjacent pyrimidines (typically thymines, but occasionally cytosines) in a single DNA strand, caused by UV exposure
• Depurination: the hydrolytic removal of guanine or adenine from the #1 carbon of deoxyribose in a DNA strand
• Deamination: the hydrolytic removal of amino (\(-NH_2\)) groups from guanine (most common), cytosine, or adenine
• Oxidative damage of a deoxyribose with any base (but most commonly with a purine base)
• Inappropriate methylation of any bases (but most commonly of purine bases)
• DNA strand breakage during replication or from radiation or chemical exposure