Spontaneous DNA Damage, Genome Instability, and Cancer—When DNA Replication Escapes Control

myces cerevisiae. The objective of this article is to evaluate these data and their possible implications for human cancer. history of a tumor increases the rate of chromosomal instability, the question arises of what the possible genetic culprits might be. The wide heterogeneity of gross Human cancer can be viewed as a disease of underlying chromosomal aberrations associated with human tu-genetic instability. Most, if not all human tumors dis-mors (Mitelman et al., 1994) suggests that a variety of play some form of genomic instability, including subtle different cellular processes and, hence, a great number DNA sequence alterations, gross chromosomal re-of genes might be affected. For simplicity, we can assign arrangements, aneuploidy, and gene amplifications. two major categories of mechanistically distinct events: These alterations have the potential to affect the func-those that simply affect chromosome numbers, and tion of growth-regulating genes that are associated with those that alter chromosome structure. Chromosome the malignant transformation of cells. Therefore, to un-number instabilities are found in most human malignan-derstand the early events in tumor development, we cies and likely reflect malfunction of the mitotic chromo-need to explore the origin of the genetic alterations that some segregation apparatus (Lengauer et al., 1998). are typically found in human tumors. However, changes in chromosome structure are equally The basis of genomic instability is unfaithful transmis-frequent and point to irregularities in DNA metabolic pro-sion of genetic information from a cell to its daughters. cesses rather than in chromosome distribution. Since This arises from failure of cellular functions that ensure these chromosomal aberrations usually involve breakage the accuracy of DNA transactions such as DNA replica-and rejoining of DNA segments, the underlying cause tion, DNA damage repair, or mitotic chromosome distri-seems to be related to either the generation or the repair bution. Specific functional defects can be associated of DNA strand breaks. Studies in different models have with a characteristic pattern of genomic instability. For established that treatment of cells with agents that in-example, inactivation of functions that increase the fidelity duce DNA double-strand breaks (DSB's) leads to recom-of DNA replication or eliminate mutagenic DNA lesions binational repair and can give rise to chromosomal re-enhances the rate of subtle DNA sequence alterations. arrangements (reviewed in Friedberg et al., 1995). This is illustrated by the phenotypes of postreplicative Enhanced mitotic recombination also results from meta-mismatch repair (MMR) or nucleotide excision repair bolic accumulation of DNA strand interruptions during (NER) defects. Malfunction …