Abnormal Dna Repair Contributes To Genomic Instability And Cancer Predisposition

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The ability to repair damaged DNA is fundamental to all biological processes because damaged sites in the genome can be converted to permanent mutations during DNA replication. The susceptibility of a particular cell type to carcinogenesis is related to its relative abilities to metabolize genotoxic carcinogens and to repair damaged DNA (81). Furthermore, susceptibility to genotoxic damage partially depends on the temporal relationship among DNA damage, DNA repair, and DNA replication (82). It follows that there are aspects of several normal cellular processes that can indirectly contribute to mutation in normal cells, including (1) slow repair of damaged DNA in specific gene sequences and (2) timing of replication of specific genes (83). DNA damage is repaired through one of several distinct pathways, including enzymatic reversal repair, nucleotide excision repair, and postreplication repair. An extensive review of each of these DNA repair pathways is beyond the scope of this chapter. Several excellent reviews are available for interested readers (47,84).

Genetic alterations that affect normal DNA repair mechanisms necessarily lead to an accelerated accumulation of DNA damage and mutation in affected cells. Numerous genes have been identified that encode proteins involved with DNA repair and are required for the maintenance of the stability of the genome. Mutation of any of these genes might lead to genetic instability and a mutation-prone phenotype, contributing to the multiplicity of mutations observed in human tumors (12,42). Evidence for this suggestion comes from studies of several rare genetic disorders identified in humans that involve dysfunctional DNA repair pathways. These disorders include xeroderma pigmentosum, Cockayne's syndrome, trichothiodystrophy, ataxia telangiectasia, Bloom's syndrome, and Fanconi's anemia. Of these disorders, xeroderma pigmentosum, ataxia telangiectasia, Bloom's syndrome, and Fanconi's anemia predispose affected individuals to the development of various malignancies when exposed to specific DNA-damaging agents. Patients with xeroderma pigmentosum display hypersensitivity to uv light and increased incidence of several types of skin cancer, including basal cell carcinoma, squamous cell carcinoma, and malignant melanoma (85). Patients with ataxia telangiecta-sia exhibit hypersensitivity to ionizing radiation and chemical agents and are predisposed to the development of B-cell lymphoma and chronic lymphocytic leukemias (86), and affected women demonstrate an increased risk of developing breast cancer (87,88). Patients with Fanconi's anemia demonstrate sensitivity to DNA crosslinking agents and are predisposed to malignancies of the hematopoietic system, particularly acute myelogenous leukemia (89,90). Patients with Bloom's syndrome demonstrate an increased incidence of several forms of cancer, including leukemia, skin cancer, and breast cancer (91,92). These patients exhibit chromosomal instability manifested as abnormally high levels of sister chromatid exchange (93).

The molecular basis of several of these genetic DNA repair deficiencies has been partially determined through genetic complementation analyses. Each complementation group identified represents a different genetic defect that eliminates a specific functional aspect of a DNA repair pathway. Seven complementation groups have been identified for xeroderma pigmentosum (94), four complementation groups have been identified for ataxia telangiectasia (95), and four complementation groups have been identified for Fanconi's anemia (96). The molecular defect in Bloom's syndrome has been suggested to involve faulty regulation of DNA repair processes rather than faulty DNA repair enzymes (97). The candidate Bloom's syndrome gene product is an enzyme with helicase activity (98). Candidate genes for each of the xeroderma pigmentosum complementation groups have now been cloned. Each of these genes encode proteins involved with various aspects of DNA nucleotide excision repair, including proteins that function in the recognition of DNA damage and factors that couple the processes of transcription and repair (99). A candidate ataxia telangiectasia susceptibility gene (termed ATM) has been identified, cloned, and characterized (100). The ATM gene product is similar to several mammalian phosphotidylinositol kinases that are involved in mitogenic signal transduction, meiotic recombination, and cell cycle control (101).

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