Principles of Biochemistry, Volume 3 - A. Lehninger 1985

Molecular Mechanisms of Genetic Information Transfer
More About Genes: Repair, Mutation, Recombination, and Cloning
Damage caused by environmental chemical agents can also be repaired

DNA damage can also be caused by reactive environmental chemical compounds that originate from human industrial activity. While these substances may not be harmful in themselves, metabolic processes can convert them into compounds that are dangerous to Cells. There are three MAIN TYPES OF such chemical agents: 1) deaminating agents—primarily nitrous acid (HNО₂) or substances that can lead to The formation of nitrous acid or nitrites during METABOLISM, 2) alkylating agents, and 3) compounds that can substitute for normal DNA bases in the molecule due to their structural similarity (Fig. 30-5).

Nitrous acid, generated from organic precursors such as nitrosamines, as well as from nitrites and nitrates, is a compound capable of very efficiently removing amino groups from cytosine, adenine, and guanine (Fig. 30-6). Nitrous acid strongly accelerates the deamination of cytosine, leading to the appearance of uracil within the DNA; we have already discussed this type of damage above. Similarly, deamination induced by nitrous acid converts adenine into hypoxanthine and guanine into xanthine (Fig. 30-6). The resulting hypoxanthine and xanthine residues in DNA are recognized and excised by specific Enzymes, after which repair is completed by DNA polymerase I and DNA ligase; The Essence of this process is illustrated in Fig. 30-4 using the removal of uracil residues as an example. Nitrates and nitrites are added as preservatives to sausages and other meat products; however, whether they are completely harmless to humans remains a matter of debate. Other precursors of nitrous acid are widely used in industry.

Certain bases in DNA can undergo modifications upon exposure to alkylating agents; for instance, highly reactive dimethyl sulfate (Fig. 30-5) methylates guanine residues. This yields O⁶-methylguanine (Fig. 30-7), which is unable to base-pair with guanine's usual partner, cytosine. Both in Bacteria and in animal Tissues, enzymes exist that specifically remove O⁶-methylguanine and replace it with normal guanine. Here, too, repair proceeds via a "cut-and-patch" mechanism similar to the one shown in Fig. 30-4.

Although numerous other pathways of DNA Repair have been discovered, the Examples given are sufficient to demonstrate how specific repair enzymes help preserve the genetic identity of Chromosomes across every species of Organism. Cells contain many enzymes capable of correcting DNA damage, yet there are no enzymes capable of repairing damaged RNA. This can presumably be explained by the fact that preserving The nucleotide sequence of DNA is vital for the survival of the species, whereas preserving the nucleotide sequence of RNA is critical only for the individual Cell in which the damaged or incorrectly synthesized RNA molecule resides.

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Fig. 30-5. Several chemical agents capable of altering the Structure of Purine or pyrimidine bases in DNA. Such compounds are termed mutagens because the consequences of their action, if left uncorrected, can cause permanent, heritable changes. A. The most active deaminating agent is nitrous acid, which can be generated from various precursors. B. Alkylating agents target bases by transferring an alkyl group to a reactive oxygen or nitrogen atom, thereby altering the base's complementary properties. C. Base analogs induce Mutations by substituting for normal bases during DNA Synthesis, leading to base-mispairing. Toxic or abnormal groups are shown in red.

Fig. 30-7. Methylation of guanine (enol form) by an active methylating agent. This methylation alters the ability of guanine to properly pair with its complementary base, resulting in the formation of an incorrect base pair.