DNA: Proofreading and Repairing


Source: Urry, Lisa A.. Campbell Biology (p. 327). Pearson Education. Kindle Edition.

Campbell Biology

We cannot attribute the accuracy of DNA replication solely to the specificity of base pairing. Initial pairing errors between incoming nucleotides and those in the template strand occur at a rate of one in 100,000 nucleotides. However, errors in the completed DNA molecule amount to only one in 10 billion nucleotides, an error rate that is 100,000 times lower. This is because during DNA replication, many DNA polymerases proofread each nucleotide against its template as soon as it is covalently bonded to the growing strand. Upon finding an incorrectly paired nucleotide, the polymerase removes the nucleotide and then resumes synthesis. (This action is similar to fixing a texting error by deleting the wrong letter and then entering the correct one.)

Mismatched nucleotides sometimes evade proofreading by a DNA polymerase. In mismatch repair, other enzymes remove and replace incorrectly paired nucleotides that have resulted from replication errors. Researchers highlighted the importance of such repair enzymes when they found that a hereditary defect in one of them is associated with a form of colon cancer. Apparently, this defect allows cancer-causing errors to accumulate in the DNA faster than normal.

Incorrectly paired or altered nucleotides can also arise after replication. In fact, maintenance of the genetic information encoded in DNA requires frequent repair of various kinds of damage to existing DNA. DNA molecules are constantly subjected to potentially harmful chemical and physical agents, such as X-rays. In addition, DNA bases may undergo spontaneous chemical changes under normal cellular conditions. However, these changes in DNA are usually corrected before they become permanent changes—mutations—perpetuated through successive replications. Each cell continuously monitors and repairs its genetic material. Because repair of damaged DNA is so important to the survival of an organism, it is no surprise that many different DNA repair enzymes have evolved. Almost 100 are known in E. coli, and about 170 have been identified so far in humans.

Most cellular systems for repairing incorrectly paired nucleotides, whether they are due to DNA damage or to replication errors, use a mechanism that takes advantage of the base-paired structure of DNA. In many cases, a segment of the strand containing the damage is cut out (excised) by a DNA cutting enzyme—a nuclease—and the resulting gap is then filled in with nucleotides, using the undamaged strand as a template. The enzymes involved in filling the gap are a DNA polymerase and DNA ligase. One such DNA repair system is called nucleotide excision repair.

An important function of the DNA repair enzymes in our skin cells is to repair genetic damage caused by the ultraviolet rays of sunlight. One type of damage is the covalent linking of thymine bases that are adjacent on a DNA strand. Such thymine dimers cause the DNA to buckle and interfere with DNA replication. The importance of repairing this kind of damage is underscored by a disorder called xeroderma pigmentosum (XP), which in most cases is caused by an inherited defect in a nucleotide excision repair enzyme. Individuals with XP are hypersensitive to sunlight; mutations in their skin cells caused by ultraviolet light are left uncorrected, often resulting in skin cancer. The effects are extreme: Without sun protection, children who have XP can develop skin cancer by age 10.

Source:

Urry, Lisa A.. Campbell Biology (p. 327). Pearson Education. Kindle Edition.

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