Chapter 9 Chapter 9 Guardians of the Genetic Text: DNA Repair and Its Malfunctions

As we described in the previous chapter, defects in two growth-controlling genes in the colon—oncogenes and tumor suppressor genes—result in the initiation of tumors and their subsequent development.Both types of genes play a key role in the development of many tumors; so far, bladder tumors, lung cancer, brain tumors and breast cancer are known to be the same.Within the next decade, this rule will extend to tumors in virtually all tissues of the body.Undoubtedly, different types of tumor cells have different mutation genes.We already know that the oncogenes and tumor suppressor genes that lead to the development of breast and colon cancers are very different.But all kinds of cancers have a common law: the malignant growth of human cancer cells is caused by the activation of oncogenes and the inactivation of tumor suppressor genes.

Recently, however, other genes have been found to play important roles in the development of cancer.In their normal stages, these genes are not responsible for cell reproduction.Their respective tasks in the cell are very different: they either directly or indirectly ensure the unity of the cell's DNA.If they fail to do their job, they will lead to the accumulation of a large number of mutated genes in the cell's genome, especially including the growth control genes mentioned above.The overall progression of cancer development is accelerating as a result of increasing mutation rates in growth-controlling genes, resulting in a substantial increase in the number of tumors in an individual's lifetime.

The genetic text stored in the DNA sequences of human cells is always vulnerable.Through diet or smoking, there are many chemical carcinogens that enter the body, end up in our cells, and then wreak havoc on cellular DNA molecules.The vast majority of dietary mutagens are natural components of food rather than man-made contamination.Ames documents dozens of natural foods, from brewed coffee to celery stalks and bean sprouts, all rich in potent natural mutagen. Furthermore, as described by Ames and others, the normal daily energy metabolism of cells releases millions of reactive molecular by-products.Many of these are oxidants and "free radicals," which contain highly reactive unpaired electrons.Like external mutagenic agents, these internal molecules can also chemically change the molecular structure in cells and DNA. The information content of DNA is again threatened with tampering.

Most active molecules are intercepted and neutralized by the diligent population of protective molecules that the cell uses to defend itself against attack.Among the protective molecules are natural antioxidants like vitamin C.Cells also produce a plethora of enzymes to neutralize and detoxify harmful molecules before they run amok and create genetic chaos. Some people maintain high levels of detoxifying enzymes, while others produce much less.This genetic difference allowed us to understand the role of these enzymes in protecting cells from various carcinogens.For example, are individuals with lower levels of protective enzymes more likely to develop cancer than those with higher levels?

Indeed, some surprising differences were found.The same smokers, those with low levels of NAT enzyme (N-acetate transferase), the incidence of bladder cancer is two and a half times the incidence of bladder cancer is higher than those of people with high levels of NAT enzyme.Low levels of another detoxifying enzyme, GSTMI (glutathione-S-transferase MI), have led to a three-fold increase in the incidence of lung cancer.The findings could one day allow us to estimate a smoker's risk of disease based on their lifetime cigarette consumption and their levels of detoxifying enzymes. Some mutagens successfully bypass these complex protective mechanisms.After escaping inactivation, these mutagenic substances interact with the DNA molecules in the cell's chromosomes, causing the DNA molecules to be damaged.Every human cell is subjected to thousands of such mutagen attacks every day.Yet despite the intense firepower, the cellular DNA remained relatively intact throughout the day.The inconsistency here needs to be explained.

A close examination of the mechanism by which a cell replicates its own DNA molecules reveals similar inconsistencies.Cells copy DNA in preparation for division, a process that is prone to errors.After DNA polymerase -- the enzyme that serves DNA replication -- has copied a stretch of DNA, 1 out of every 1,000 bases in the new strand of DNA at that point is wrong due to a mishandling of the polymerase.As before, however, the actual rate of mutants accumulating in the DNA remains extremely low.Somehow, cells eliminate most of the original replication errors in their DNA. The actual number is very low: by the time the cell has completed the full DNA replication process, less than one in a million bases has been copied incorrectly.Inside the cell is a copy-editing mechanism that looks for mis-duplicated bases in the DNA and ejects them from the double helix.Such a low mutation rate is a testament to the power of the mechanism.Gaps left by the exiled bases are replaced by new bases that restore the correct sequence of DNA, erasing all errors without leaving a trace.There is a similar mechanism in the cell that is responsible for finding and cutting out DNA bases that have been attacked and altered by chemical mutagens.These processes of restoring genetic text are called "DNA repair".

So the indestructibility and impregnability of the cell's genetic database is just a mirage.The stability of the genome is like a trembling high-wire performance, a never-ending protracted battle between hypervigilant repair mechanisms and genetic chaos. This situation has a direct impact on tumor formation: If DNA repair efforts are in vain, a large number of altered bases accumulate in the cellular DNA.This means that the accumulation of mutations is affected by at least three factors: damage to DNA by external or internal mutagen, errors in DNA replication, and the presence of DNA repair mechanisms that compensate for damage caused by mutagenic substances or replication errors defect.Since mutations are the engine of tumors, all three of these factors are likely to be the cause of tumors to some extent.

We now know that several familial cancers are caused by genetic defects in DNA repair. The cellular machinery of DNA repair consists of large groups of proteins.Among them, some proteins are responsible for recognizing damaged DNA fragments, some are responsible for cutting, and some replace the deleted wrong bases with new bases that can restore the correct sequence.A defect in a gene that specifies the protein's structure kicks cancer into high gear. There is a well-known case associated with hereditary colon cancer, which is four to five times more common than familial polyposis.One of the genes inherited by patients with hereditary nonpolyposis colon cancer (HNPCC) is defective in four genes that regulate key DNA repair proteins.All four proteins are critical in the mechanisms that repair DNA replication errors.As mentioned above, many replication errors are quickly erased by replacing the mis-duplicated bases with the correct ones.In cells from HNPCC patients, however, many of these replication errors were not corrected and were passed on to daughter cells intact as mutations as the cells divided.As a result, the cells of HNPCC patients accumulated mutations at alarming rates as the cells grew and divided over and over again.

Cells throughout the body of HNPCC patients are deficient in DNA repair.Despite the ubiquity of the defect, the cancers were most concentrated in the colon and the endometrial wall; other sites, such as the ovaries and bladder, were less frequent.Why cancer has a soft spot for these organs is unknown. Colon tumors that occur in patients with HNPCC carry mutated oncogenes and tumor suppressor genes that closely resemble those in patients with sporadic, nonfamilial cancers.The main difference is the rate at which the respective genes mutate. In the colon cells of HNPCC patients, the rate of mutations in these genes and the overall rate of tumor development skyrocket due to the absence of efficient DNA repair mechanisms.

Among the various DNA repair enzymes, some specialize in recognizing damage caused by ultraviolet light (UV).Ultraviolet rays produced by the sun or brown skin lamps are short-wave radiation that attack DNA molecules, causing adjacent bases on the DNA chain to fuse into weird two-base complexes, causing obvious damage to skin cells.These base fusions lead to replication errors, cumulative mutations, and, as a result, basal cell or squamous cell skin cancers.These two diseases are easily curable, but the accumulation of mutations can also lead to incurable diseases such as melanoma. The incidence of skin cancer has increased day by day in recent years.In the past 20 years, the incidence of melanoma has also increased by about 4% per year.The main culprit for the increase in morbidity should undoubtedly be the rampant sunbathing of the past thirty or forty years.The use of the tan room is sure to add fuel to the fire.People who are repeatedly exposed to high doses of ultraviolet light, whether intentionally or not, are not immune to the accumulation of mutated cells in their skin, despite the hard work of their DNA repair mechanisms.

About 10 genes are specifically responsible for repairing DNA damage caused by ultraviolet light, and genetic defects in one of these genes cause a rare disease called xeroderma pigmentosa.The patient's skin is extremely sensitive to sunlight and prone to skin cancer.Patients with xeroderma pigmentosa must strictly avoid direct exposure to sunlight and shield their skin for a long time to prevent canceration. Another DNA repair gene, A7”M, if genetically deficient, is extremely sensitive to ionizing radiation or X-rays. Hypersensitivity is just one of many defects in DNA repair, and is just the tip of the iceberg; Mutations accumulate at an accelerated rate. ATM gene defects can have several manifestations.Individuals who inherit two copies of the defective A7"M gene develop ataxia-telangiectasia syndrome. 1 in 50,000 people pay a high price for this DNA repair defect. They Postural instability, vasodilation, immunodeficiency, premature aging, and a 100-fold increased risk of cancer. Recent evidence has shown that two genes, BRCAI and BRCAZ, are involved in familial breast and ovarian cancers, which are responsible for other proteins that maintain DNA integrity.A genetic defect in one of these genes causes 10 percent of breast cancers in the United States.As with other inherited DNA repair deficiencies, why do the two mutated genes favor certain target organs—breasts and ovaries?The reason is still unknown. We have not yet understood the full intricacies of the DNA repair machinery.Likewise, we do not know the extent and frequency of defective repair gene distribution.Someday, when these two questions are fully understood, it will be possible to identify the role of DNA repair defects in various human tumors. A subset of enzymes is responsible for neutralizing foreign mutagens, such as those introduced into the body by smoking.The problem with these enzymes is more complicated.Unraveling their role in defending the genome against chemical attack, and the consequences of low levels of enzymes in cells, may take another decade.