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DAMAGE'

REPAIR

DNA REPLICATION

MUTATION FIXATION

TRANSFORMED CELL UNCONTROLLED GROWTH TUMOR METASTASIS

MUTANT GENE GENETIC DISEASE

ACCELERATED AGING CELL DEATH

When that amino group is lost, either through spontaneous, chemical, or enzymatic hydrolysis, a uracil (U) base is formed, and a normal C-G DNA base pair is changed to a premutagenic U-G base pair (uracil is not a normal part of DNA).

The U-G base pair is called premutagenic because if it is not repaired before DNA replication, a mutation will result. During DNA replication, the DNA strands separate, and each strand is copied by a DNA polymerase protein complex. On one strand, the uracil (U) will pair with a new adenine (A), while on the other strand the guanine (G) will pair with a new cytosine (C). Thus, one DNA double-strand contains a normal C-G base pair, but the other double-strand has a mutant U-A base pair. This process is called mutation fixation, and the mutation of the G to an A is said to be fixed (meaning "fixed in place," not "repaired"). In other words, the cell now accepts the new mutant base pair as normal. It is estimated that approximately 400 cytosine deamination events per genome occur every day. Clearly, it is very important for the cell to repair DNA damage before DNA replication commences, in order to avoid mutation fixation. One cause of

Figure 2. If damaged DNA (*) is not repaired, the mistake (mutation) can be replicated and become permanent (fixed) in the genome. This may cause severe problems.

polymerase enzyme complex that synthesizes DNA or RNA from individual nucleotides mutagen any substance or agent capable of causing a change in the structure of DNA

hormone molecule released by one cell to influence another endogenous caused by factors inside the organism excision removal catalyze aid in the reaction of normal human aging is the gradual accumulation over time of mutations in our cellular DNA.

Alkylation. Another type of base modification is alkylation (Figure 2C). Alkylation occurs when a reactive mutagen transfers an alkyl group (typically a small hydrocarbon side chain such as a methyl or ethyl group, denoted as -CH3 and -C2H5, respectively) to a DNA base. The nitrogen atoms of the purine bases (N3 of adenine and N7 of guanine) and the oxygen atom of guanine (O6) are particularly susceptible to alkylation in the form of methy-lation. Methylation of DNA bases can occur through the action of exogenous (environmental) and endogenous (intracellular) agents. For example, exogenous chemicals such as dimethylsulfate, used in many industrial processes and formed during the combustion of sulfur-containing fossil and N-methyl-N-nitrosoamine, a component of tobacco smoke, are powerful alkylating agents. These chemicals are known to greatly elevate mutation rates in cultured cells and cause cancer in rodents.

Inside every cell is a small molecule known as S-adenosylmethionine or "SAM." SAM, which is required for normal cellular metabolism, is an endogenous methyl donor. The function of SAM is to provide an activated methyl group for virtually every normal biological methylation reaction. SAM helps to make important molecules such as adrenaline, a hormone secreted in times of stress; creatine, which provides energy for muscle contraction; and phosphatidylcholine, an important component of cell membranes. However, SAM can also methylate inappropriate targets, such as adenine and guanine. Such endogenous DNA-alkylation damage must be continually repaired; otherwise, mutation fixation can occur.

Oxidation. Oxidative damage to DNA bases occurs when an oxygen atom binds to a carbon atom in the DNA base (Figure 2D). High-energy radiation, like X rays and gamma radiation, causes exogenous oxidative DNA base damage by interacting with water molecules to create highly reactive oxygen species, which then attack DNA bases at susceptible carbon atoms. Oxidative base damage is also endogenously produced by reactive oxygen species released during normal respiration in mitochondria, the cell's "energy factories."

Humans enjoy a long life span; thus, it would seem that healthy, DNA repair-proficient cells could correct most of the naturally occurring endogenous DNA damage. Unfortunately, when levels of endogenous DNA damage are high, which might occur as the result of an inactivating mutation in a DNA repair gene, or when we are exposed to harmful exogenous agents like radiation or dangerous chemicals, the cell's DNA repair systems become overwhelmed. Lack of DNA repair results in a high mutation rate, which in turn may lead to cell death, cancer, and other diseases. Also, if the level of DNA repair activity declines with age, then the mutational burden of the cell will increase as we grow older.

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