Mechanisms of clastogen-induced chromosomal aberrations: a critical review and description of a model based on failures of tethering of DNA strand ends to strand-breaking enzymes.
Most theories of the mechanisms of chromosomal aberrations involve the concepts of clastogens directly acting on DNA to produce strand breaks, and subsequently, the survival of these directly caused DNA strand breaks - or misrepairs of them - through to metaphase when they appear as chromosomal 'breaks' or translocations. Nevertheless, various observations are inconsistent with these theories such as the fact that many chemical clastogens (e.g. caffeine, acridines) do not covalently react with DNA, while almost all of the chemical clastogens (e.g. alkylating agents) which do react covalently with DNA, do not directly cause DNA strand breaks. This paper reviews the 'direct-clastogen damage to DNA' theories, and the phenomenology of chromosomal aberrations which are inconsistent with them. Then the theory is considered that the breaks in chromosomes seen at metaphase and anaphase are not the survivors of DNA breaks directly induced by clastogens, but rather derive from breaks created by the enzymes which repair damaged DNA. After that, newer knowledge is reviewed that (i) strand breaks are created during normal DNA unravelling (by topoisomerases), during DNA synthesis, and during DNA repairs, and these breaks can be single- or double-stranded, (ii) breaks variously associated with unravelling, synthesis and repair can occur 'anywhere, anytime' (pre-synthesis, synthesis or post-synthesis) in the cell cycle, and (iii) the enzyme assemblies for DNA unravelling, synthesis and repair which make and religate the breaks must be non-covalently tethered to the ends of the DNA strands while the breaks created by the enzymes are in existence. It is then suggested that all the morphological types and other phenomena of chromosomal aberrations can be explained by aspects, mechanisms and effects of failures of this tethering function. Circumstances involving the basic mechanism (failure of DNA-end-tethering function while enzyme-created breaks are in existence) are described which might result in 'gaps', translocations ('exchanges'), complex lesions such as 'triradials', as well as in 'minutes', amplifications and inversions. Predictions are made concerning likely results in various suggested studies including those involving sensitive assays for DNA-end-to-enzyme tethering functions in vitro.
Bignold
L P
LP
Division of Surgical Pathology, Institute of Medical and Veterinary Science, P.O. Box 14, Rundle Mall, Adelaide, SA 5001, Australia. Electronic address: leon.bignold@adelaide.edu.au.
D000818:Animals; D002869:Chromosome Aberrations / Q000187:drug effects*; D004247:DNA / Q000378:metabolism*; D053960:DNA Breaks / Q000187:drug effects*; D045643:DNA Repair Enzymes / Q000378:metabolism*; D006801:Humans; D008957:Models, Genetic; D009153:Mutagens / Q000633:toxicity*
D009153:Mutagens; D004247:DNA; D045643:DNA Repair Enzymes