DNA Damage, DNA Repair and Induced Mutagenesis: Some Enzymological and Structural Considerations

Abstract

The particular interest of this symposium is to review all relevant knowledge which may help in the assessment of carcinogenic and mutagenic risk, in particular the risk arising from diverse environmental and metabolic conditions. Of special interest are the origins of somatic and germ line mutations. A priori, the majority of deleterious mutations are recessive, which as germ line mutations may cause more victims than the dominant mutations. The reason is that the majority of dominant mutations are readily recognized in the first carrier; either their propagation is directly stopped in the case of lethal mutations or they can be controlled in the case of non-lethal mutations. Recessive mutations are usually not recognized either in the first carrier or in later heterozygous carriers and they thus spread in the population repeatedly causing victims among the homozygous progeny. Homozygosity arises in the offspring of heterozygous parents by the Mendelian rule of random chromosome assortment. Homozygous somatic cell lineages can arise in heterozygous individuals by chromosomal rearrangements (mitotic recombination, deletion, non-disjunct ion). Since the normal human population contains roughly 1% heterozygous carriers for any given recessive gene mutation, a normal individual may carry on the order of 10³ diverse recessive mutations, some of which when homozygous may cause severe cellular metabolic defects including cancerous growth.¹ Therefore, when trying to estimate risk from carcinogenic and other deleterious mutations, one cannot underestimate the role of chromosomal rearrangement in expression of pre-existing as well as of newly arising recessive mutations.¹ Early routine detection of recessive (and other) mutations in humans may become possible through development of new sensitive molecular probes.

This paper is dedicated to Professor Maurice Errera on the occasion of his 70th birthday and of his retirement as the director of the Laboratoire de Biophysique et Radiobiologie of the Universite Libre de Bruxelles The majority of the work reviewed here was carried out in the “Service Errera”.