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 chemicals in the environment. Although it is often difficult to ascertain the relative contributions to biological endpoints from endogenous vs. environmental sources of genomic instability, such determinations are highly relevant to risk estimates based upon perceived toxic levels of environmental agents. Of particular concern are the DNA lesions caused by reactive oxygen species that are generated both as a byproduct of oxidative metabolism and as a consequence of exposure to ionizing radiation and some other toxicants. We need to better understand the sequence of biochemical events that occurs between the initial formation of a DNA lesion and the biological outcome. These events may include transcription, replication, and cell cycle regulation, as well as DNA repair. 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 polymerase at a lesion may block access of repair enzymes, and it may also serve as a signal for upregulation of repair enzymes, cell cycle arrest and/or apoptosis. Our current understanding of the role of transcription in lesion processing and biological outcomes will be summarized, with particular emphasis upon the information gained from characterization of human genetic diseases expressing defects in the processing of damaged DNA. In some cases, the clinical features of these diseases might be understood in terms of deficiencies in the repair of lesions that arrest transcription.
Hanawalt
P C
PC
Department of Biological Sciences, Stanford University, Stanford, CA 94305-5020, USA. hanawalt@leland.stanford.edu
D000818:Animals; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D004781:Environmental Exposure / Q000009:adverse effects*; D030342:Genetic Diseases, Inborn / Q000235:genetics; D016678:Genome; D006801:Humans; D016296:Mutagenesis / Q000235:genetics