Mobile genetic element activation and genotoxic cancer therapy: potential clinical implications.
DNA Transposable Elements
Approximately one-quarter of the human genome is composed of short and long interspersed elements (SINEs and LINEs, respectively). These elements have spread throughout the genome by a process termed retrotransposition, consisting of transcription of an element into RNA, reverse transcription into cDNA, and reinsertion of the copied element into a new genomic location. Recombination events involving these elements, including novel insertions into active genes, have been associated with a number of human diseases. Despite the fact that these elements have replicated to hundreds of thousands of copies in the genome, under most conditions they remain transcriptionally silent, and therefore are not actively replicating. The signals controlling retrotransposable element activation in the genome have not been defined. Our laboratory recently found that exposure of cells to a variety of DNA-damaging agents, including several common chemotherapeutic drugs and gamma-radiation, is associated with dramatic induction of SINE transcription, and of a concomitant endogenous reverse transcriptase activity. As SINEs do not encode for reverse transcriptase, the latter finding suggests a more global activation of retrotransposable elements in response to DNA damage. Together these observations suggest that genotoxic exposure may lead to genomic mutation not only through direct DNA damage, but also through indirect activation of potentially mutagenic mobile elements in the genome. The nonrandom distribution of retrotransposable elements in the human genome may contribute to the pattern of characteristic translocation events associated with secondary malignancies in patients exposed to genotoxic agents. Here we describe these and other mechanisms by which retrotransposable elements can contribute to disease, and present an overview of what is known about this large, and largely unexplored, segment of the genome. Understanding the cellular responses to genotoxic stress may permit the development of a means of predicting the risks and preventing the development of secondary malignancy following cancer therapy.