DNA Repair Defects

DNA repair mechanisms are involved in maintaining the integrity of DNA, which often acquires errors during replication. When the cellular mechanisms that repair errors in the DNA are damaged — through acquired or inherited alterations — the rate of genetic mutation increases by several orders of magnitude.

Defects in two mismatch repair genes, called MSH2 and MLH1, underlie one of the most common syndromes of inherited cancer susceptibility, hereditary nonpolyposis colon cancer. This form of colon cancer accounts for 15 to 20 percent of all colon cancer cases. Inherited or acquired alterations in the mismatch repair genes allow mutations — specifically point mutations and changes in the lengths of simple sequence repetitions — to accumulate rapidly (behaviour referred to as a mutator phenotype). Since this defect is inherited by all the cells in the body, it is not known why some organs are more susceptible to cancer development than others.

Another type of repair system that can malfunction is one that corrects defects inflicted on DNA by ultraviolet radiation, a major constituent of sunlight (see the section Cancer-causing agents: Radiation). This kind of radiation damage involves the fusion of two nucleotide bases called pyrimidines to form a ''pyrimidine dimer.'' Normally, the repair system removes the dimer from the DNA and replaces it with two undamaged nucleotides. Malfunction of the repair pathway, on the other hand, is responsible for two inherited disorders, xeroderma pigmentosum and Cockayne syndrome.

Many cells undergo programmed cell death, or apoptosis, during fetal development. Apoptosis also may occur when a cell becomes damaged or deregulated, as is the case during tumour development and other pathological processes. Thus, when functioning properly, the body can induce apoptosis to rid itself of cancer cells.

Not all cancer cells succumb in this manner, however. Some find ways to escape apoptosis. Two mutations identified in human tumours lead to a loss of programmed cell death. One mutation inactivates the p53 gene, which normally can trigger apoptosis. The second mutation affects a proto-oncogene called bcl-2, which codes for a protein that blocks cell suicide. When mutated, the bcl-2 gene produces excessive amounts of the bcl-2 protein, which prevents the apoptosis program from being activated. Malignant lymphomas that stem from B lymphocytes exhibit this bcl-2 behaviour. The alteration of the bcl-2 gene is caused by a chromosomal translocation that keeps the gene in a permanent ''on'' position. Loss of p53 function protects cells from only certain kinds of suicide, whereas the bcl-2 alteration completely blocks access to apoptosis.

The blocking of apoptosis is thought to be an important mechanism in tumour generation. This mutation also may contribute to the development of tumours that are resistant to radiation and drug therapies, most of which destroy cancer cells by inducing apoptosis in them. If some cells within a tumour are unable to commit suicide, they will survive treatment and proliferate, creating a tumour refractory to therapy of this type. In this way apoptosis-inducing therapies may actually select for cancer cells resistant to apoptosis.

Immortalization is another way that cells escape death. Normal cells have a limited capacity to replicate, and so they age and die. The processes of aging and dying are regulated in part by DNA segments called telomeres, which are found at the ends of chromosomes. Telomeres shorten every time chromosomes are replicated and the cell divides. Once they have been reduced to a certain size, the cell reaches a crisis point, is prevented from dividing further, and dies.

This form of growth control appears to be inactivated by oncogenic expression or tumour suppression activity. In cells undergoing malignant transformation, telomeres do shorten, but, as the crisis point nears, a formerly quiescent enzyme called telomerase becomes activated. This enzyme prevents the telomeres from shortening further and thereby prolongs the life of the cell.

Most malignant tumours — including breast, colon, prostate, and ovarian cancers — exhibit telomerase activity, and the more advanced the cancer, the greater the frequency of detectable telomerase in independent samples. If cell immortality contributes to the growth of most cancers, telomerase would appear to be an attractive target for therapy.