Mitotic recombination is an important mutational event following oxidative damage.
The mutagenic effects of hydrogen peroxide (H(2)O(2)), a source of reactive oxygen species (ROS) have been determined in human lymphocytes. T-lymphocytes mutated at the autosomal HLA-A locus on chromosome 6 have been clonally isolated (N = 2097 clones) and the molecular basis of each clonal mutation characterised as due to intragenic, deletion or mitotic recombination mutation. H(2)O(2) caused a dose dependent increase in mutation frequency. There was no significant increase in the frequency of intragenic mutations. Mitotic recombination (MR) was responsible for 87% of the increase in mutation frequency induced by H(2)O(2) and gene deletion was responsible for 13%. MR results in loss of heterozygosity (LOH) distal to the recombination site. It is known that LOH is important in the initiation and progression of cancer. These results suggest that the biologically important consequence of some ROS may be LOH as a by-product of recombination repair. They also suggest that if our observations apply to ROS generally, then many of the mutations which accumulate with ageing or which are observed in cancer may be due to factors other than ROS.
Turner
David R
DR
Department of Haematology and Genetic Pathology, School of Medicine, Flinders University, GPO Box 2100, Adelaide 5001, Australia. david.turner@flinders.edu
Dreimanis
Monica
M
Holt
Deborah
D
Firgaira
Frank A
FA
Morley
Alexander A
AA
D004249:DNA Damage; D015234:HLA-A Antigens / Q000187:drug effects / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects; D018384:Oxidative Stress / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011995:Recombination, Genetic
D015234:HLA-A Antigens; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide