Homologous Recombination - Effects of Dysfunction

Effects of Dysfunction

Without proper homologous recombination, chromosomes often incorrectly align for the first phase of cell division in meiosis. This causes chromosomes to fail to properly segregate in a process called nondisjunction. In turn, nondisjunction can cause sperm and ova to have too few or too many chromosomes. Down's syndrome, which is caused by an extra copy of chromosome 21, is one of many abnormalities that result from such a failure of homologous recombination in meiosis.

Deficiencies in homologous recombination have been strongly linked to cancer formation in humans. For example, each of the cancer-related diseases Bloom's syndrome, Werner's syndrome and Rothmund-Thomson syndrome are caused by malfunctioning copies of RecQ helicase genes involved in the regulation of homologous recombination: BLM, WRN and RECQ4, respectively. In the cells of Bloom's syndrome patients, who lack a working copy of the BLM protein, there is an elevated rate of homologous recombination. Experiments in mice deficient in BLM have suggested that the mutation gives rise to cancer through a loss of heterozygosity caused by increased homologous recombination. A loss in heterozygosity refers to the loss of one of two versions—or alleles—of a gene. If one of the lost alleles helps to suppress tumors, like the gene for the retinoblastoma protein for example, then the loss of heterozygosity can lead to cancer.

Decreased rates of homologous recombination cause inefficient DNA repair, which can also lead to cancer. This is the case with BRCA1 and BRCA2, two similar tumor suppressor genes whose malfunctioning has been linked with considerably increased risk for breast and ovarian cancer. Cells missing BRCA1 and BRCA2 have a decreased rate of homologous recombination and increased sensitivity to ionizing radiation, suggesting that decreased homologous recombination leads to increased susceptibility to cancer. Because the only known function of BRCA2 is to help initiate homologous recombination, researchers have speculated that more detailed knowledge of BRCA2's role in homologous recombination may be the key to understanding the causes of breast and ovarian cancer.