The earth formed about 4.65 billion years ago, and life began to evolve on earth about a billion years after the earth formed—the earliest forms of bacteria are found in rocks that are 3.5 billion years old (10). The earth was far more radioac­tive at that time, and there was much more radiation coming from space because there was less atmosphere to block it. Therefore, life evolved in an environment of high levels of radiation. In light of this fact, it should not be surprising that bac­teria that developed repair mechanisms to cope with the damage to DNA caused by the radiation would be selected for over time by evolution. Eukaryotic cells, including fungi such as yeast and higher eukaryotes such as mammalian cells, evolved later with even more sophisticated processes to repair DNA. As a result, we are actually quite resistant to radiation because our cells have been coping with it for a long time!

Let us briefly consider the types of repair pathways that exist to repair DNA damage. There are three basic types of repair—mismatch repair, excision repair, and double strand break repair (11). Mismatch repair is a very important proof­reading type of repair that makes sure that the DNA gets replicated correctly. The four bases—adenine (A), cytosine (C), guanine (G), and thymine (T)—have to pair properly when DNA is replicated: normally A can only pair with T and G can only pair with C. Occasionally, the wrong pairs form, so mismatch repair enzymes identify these, take out the wrong base, and replace it with the correct one. This can only happen shortly after DNA replication occurs. Mismatch repair is not related to radiation damage, but it is very important to avoid random mutations from normal DNA replication. Mutations in the genes for this type of repair often end up causing colon cancer.

There are two forms of excision repair—nucleotide excision and base excision. Nucleotide excision repair is primarily involved with repairing damage from UV radiation from the sun. UV radiation causes a chemical reaction that binds adja­cent thymine bases together, forming a T-T bond called a thymine dimer. These thymine dimers are excised by enzymes that identify the bulge they make in DNA, then cut out about 24-32 nucleotides2 from the surrounding DNA and fill in the gap with the right nucleotides. Mutations in these repair genes often end up caus­ing skin cancer. Individuals who have a genetic syndrome known as Xeroderma pigmentosum have mutations in nucleotide excision repair genes, and they are extremely sensitive to UV light.

Base excision repair is capable of repairing a wide variety of damage to bases from radiation. Cells have a large number of specific enzymes called glycosylases that identify specific types of damage to DNA bases and cut the base out while leaving the DNA strand intact. The deoxyribose sugar (the D in DNA) is then excised and a new nucleotide (the sugar and base) is inserted, completing the repair. This is a very important pathway for radiation damage, since thousands of bases are damaged by 1 Gy of radiation (11).

The most important type of repair for ionizing radiation is repair of DSBs because a double strand break is potentially catastrophic for a cell. There are two methods of repair of DSBs: non-homologous end joining (NHEJ) and homologous recombination (HR) (12, 13). NHEJ is the simplest of the methods to repair DSBs and can be thought of as simply sticking back together the “sticky ends” of broken strands of DNA. Of course, it takes a lot of cell machinery to accomplish this, but NHEJ has the capability of sticking any two broken ends of DNA back together. Thus it is very efficient, but not always accurate since it can’t tell whether the right pieces of DNA are getting stuck back together. Often there can be pieces of more than one chromosome that are broken and are in close proximity. NHEJ may fuse the wrong pieces of chromosomes back together, causing various kinds of chromosomal aberrations that can lead to cell death or sometimes cause cancer.

The other pathway for DSB repair, HR, is more complex but is very accurate. It depends on having another strand of the DNA to copy, which happens only after the DNA has replicated in what is called the synthesis or S-phase in the cell cycle. The broken DNA at the strand break is matched up with the replicated copy of the chromosome (called a chromatid); enzymes can then clean up the broken ends and copy the other chromatid exactly. This process completely repairs the DSB with no errors, but it is not always available. The majority of DSBs in human cells are repaired by the NHEJ pathway.

These various pathways for repairing DNA damage explain why one Gy of radi­ation can cause such extensive damage to the DNA yet is seldom lethal to the cell. Our cells are capable of being exposed to a surprisingly large amount of radiation with no permanent damage. This is perhaps one of the most important ideas in this book, particularly since many people think that radiation is extremely dam­aging and that exposure to even a small amount of radiation will inevitably lead to cancer. It is simply not true!

Most of the damage in chromosomes from a particles is so extensive (see Figure 7.5) that it cannot be repaired and usually ends up killing the cell. That is why the radiation weighting factor is so large for a particles (Table 7.2)—they are about 20 times more effective than electrons or у rays in damaging DNA and kill­ing cells. However, since a particles cannot penetrate through even a single layer of cells, they can only do very localized damage. The main hazard for a particles is when they are inhaled in the lungs and remain trapped. This is the reason that radon is an important factor in causing lung cancer (more about radon later). It is also why plutonium is hazardous if it is inhaled and stays in the lungs.