Gene amplification, radiation sensitivity and DNA double-strand breaks

Abstract

DNA double-strand breaks (DSBs) are one of the main types of damage induced by ionizing radiations. Free DNA ends that are not correctly repaired can be engaged in pathways triggering gene amplification. Following gene amplification the copy number of a portion of the genome is increased, leading to an enhanced expression of the genes located in the amplified region. Gene amplification plays an important role in cancer, being one of the mechanisms of oncogene activation; in addition, it can confer resistance to chemotherapeutic agents, through the increase in the copy number of genes coding for drug targets. The presence of gene amplification can have a prognostic and a diagnostic value and can help in orienting therapy in specific tumour types. The amplified DNA is primarily produced through recombination-based pathways and can be located either within chromosomes or on extra-chromosomal acentric elements. Studies on the organization of the amplified DNA in tumour cells and in cultured drug resistant cells have suggested that a single DSB can trigger a cascade of events leading to a large number of copies of a region of the genome. In addition, it has been shown that amplified DNA is unstable, further increasing the long-term effect of the initial event. Gene amplification is a peculiar feature of transformed cells and the ability to amplify is strongly influenced by the cellular genetic background. Genes involved in DNA damage response and in DNA damage repair can play a role in controlling the amplification process, in particular, it has been shown that defects in DSB repair functions can increase the frequency of gene amplification. In this review, we will discuss the biological significance of gene amplification, together with the role of DNA DSBs and DSB repair genes in the generation of amplified DNA.