GENOMIC INSTABILITY - ENVIRONMENTAL INVASION AND THE ENEMIES WITHIN

Deleterious alterations in cellular DNA result from endogenous sources of damage, as well as from external radiations and genotoxic chemical s in the environment. Although it is often difficult to ascertain the relative contributions to biological endpoints from endogenous vs. env ironmental sources of genomic instability, such determinations are hig hly relevant to risk estimates based upon perceived toxic levels of en vironmental agents. Of particular concern are the DNA lesions caused b y reactive oxygen species that are generated both as a byproduct of ox idative metabolism and as a consequence of exposure to ionizing radiat ion and some other toxicants. We need to better understand the sequenc e of biochemical events that occurs between the initial formation of a DNA lesion and the biological outcome. These events may include trans cription, replication, and cell cycle regulation, as well as DNA repai r. Heterogeneity in the intragenomic distribution of lesions and their repair must also be taken into account. Expressed genes are unusually susceptible to alteration by some agents, and preferential repair of some lesions is targeted to transcribed DNA strands. An arrested RNA p olymerase at a lesion may block access of repair enzymes, and it may a lso serve as a signal for upregulation of repair enzymes, cell cycle a rrest and/or apoptosis. Our current understanding of the role of trans cription in lesion processing and biological outcomes will be summariz ed, with particular emphasis upon the information gained from characte rization of human genetic diseases expressing defects in the processin g of damaged DNA. In some cases, the clinical features of these diseas es might be understood in terms of deficiencies in the repair of lesio ns that arrest transcription. (C) 1998 Elsevier Science B.V. All right s reserved.