STUDIES ON PHENOTYPIC COMPLEMENTATION OF ATAXIA-TELANGIECTASIA CELLS BY CHROMOSOME TRANSFER

Cells derived from patients with the cancer-prone inherited disorder a taxia-telangiectasia (A-T) show an abnormal response to ionizing radia tion-induced DNA damage, such as an increased cell killing and a dimin ished inhibition of DNA synthesis. The enhanced killing of A-T (group D) cells by X-rays can be corrected by multiple cDNAs, mapping to diff erent chromosomes (6, 11, 17, and 18). In order to examine whether gen es located on these chromosomes complement AT-D cells, normal neo-tagg ed chromosomes 6, 11, 17, and 18 were introduced into AT-D cells by mi crocell-mediated chromosome transfer. However, correction of the enhan ced killing of AT-D cells by X-rays could only be achieved by chromoso me 11 and by none of the other chromosomes tested. The enhanced killin g of A-T (complementation group C) cells was also corrected by chromos ome 11. Usually, but not in all microcell hybrid clones, chromosome 11 also corrected the radioresistant DNA synthesis (RDS) phenotype of AT -D and AT-C cells. These results (i) confirm findings by others sugges ting assignment of the ATD and ATC genes to chromosome 11, (ii) demons trate that several genes can modify the cellular radiation response wh en they are taken out of their normal genomic context and/or control, and (iii) indicate that the RDS phenotype and the enhanced cell killin g in A-T are independent pleiotropic features resulting from the prima ry mutations in A-T. Also, our findings underscore that, in establishi ng cDNAs as candidate genes for A-T, microcell-mediated chromosome tra nsfer studies are needed to exclude nonspecific correcting effects of these candidate cDNA genes.