When it comes to long-term survival and evolution, all organisms depend on a delicate balance between the processes involved in maintaining the stability of their genomes and the opposing processes that lead to destabilization. At the level of mammalian somatic cells in renewal tissues, events or conditions that may tilt this balance towards instability have aroused special interest in relation to carcinogenesis. Mutations affecting DNA (and its subsequent repair) would, of course, be an important consideration here. These can occur spontaneously through endogenous cellular processes or as a result of exposure to mutagenic environmental agents.
It is in this context that we discuss the rather unique destabilizing effects of ionizing radiation (IR) in terms of its ability to cause large-scale structural rearrangements in the genome. We present arguments that support the conclusion that these and other important effects of IR originate largely from microscopically visible chromosomal aberrations. All exogenous agents capable of producing chromosomal aberrations (CA), that is, for long-term survival and evolution, all organisms have depended on a delicate balance between the processes involved in maintaining the stability of their genomes and the opposing processes that lead to destabilization. Mutagenic events resulting from large-scale structural changes in the mammalian genome caused by IR include deletions, insertions, inversions and translocations, any of which can alter genes, alter the control of gene expression, or even result in the expression of new fusion sequences.
IR is virtually unique in its effectiveness in producing rapid double-stranded breaks (DSB) of DNA randomly throughout the genome, which is the injury necessary for the development of these structural rearrangements. To understand how ionizing radiation causes complete disruption of chromosomes, it is important to note that when two direct impacts occur on the same rung of the DNA macromolecule, it can lead to complete chromosome breakage. Symmetrical exchanges such as interarm types (pericentric inversions) and intra-arm types (paracentric inversions) are also common when it comes to chromosomal aberrations caused by IR. Asymmetric interchanges include inter-arm types where a centric ring and an associated compound acentric fragment are formed, and intra-arm types which result in an acentric ring fragment and a shortened chromosome no longer containing the deleted region previously occupied by the ring fragment expelled.
Small acentric rings are commonly referred to as interstitial (ID) deletions. Being primarily ring-type structures, they should not be confused with terminal removals which are discussed below. Inversions are transmissible and can be potential sources of inheritable IR-induced mutations including driver mutations associated with carcinogenesis. The use of advanced methodologies has enabled us to detect previously considered “cryptic” chromosomal aberrations which has impacted our basic understanding of the effects of radiation on mammalian cells.
The default assumption has always been that small base pair changes escape PCR detection but thinking in terms of exchange breakpoints suggests otherwise. Translocations or exon-targeting PCR tests could rule out this possibility and provide further insight into how ionizing radiation causes complete chromosome breakage. It is clear from this discussion that chromosomal aberrations underlie many important biological effects caused by ionizing radiation and studies related to its formation and detection are essential for understanding its mechanisms of action.
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