Studies on phenotypic complementation of ataxia-telangiectasia cells by chromosome transfer.
Cells derived from patients with the cancer-prone inherited disorder ataxia-telangiectasia (A-T) show an abnormal response to ionizing radiation-induced DNA damage, such as an increased cell killing and a diminished inhibition of DNA synthesis. The enhanced killing of A-T (group D) cells by X-rays can be corrected by multiple cDNAs, mapping to different chromosomes (6, 11, 17, and 18). In order to examine whether genes located on these chromosomes complement AT-D cells, normal neo-tagged chromosomes 6, 11, 17, and 18 were introduced into AT-D cells by microcell-mediated chromosome transfer. However, correction of the enhanced killing of AT-D cells by X-rays could only be achieved by chromosome 11 and by none of the other chromosomes tested. The enhanced killing of A-T (complementation group C) cells was also corrected by chromosome 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 suggesting assignment of the ATD and ATC genes to chromosome 11, (ii) demonstrate that several genes can modify the cellular radiation response when they are taken out of their normal genomic context and/or control, and (iii) indicate that the RDS phenotype and the enhanced cell killing in A-T are independent pleiotropic features resulting from the primary mutations in A-T. Also, our findings underscore that, in establishing cDNAs as candidate genes for A-T, microcell-mediated chromosome transfer studies are needed to exclude nonspecific correcting effects of these candidate cDNA genes.
Medical Genetics Centre--Department of Radiation Genetics and Chemical Mutagenesis, State University of Leiden, The Netherlands.
W
W
Jongmans
G W
GW
Verhaegh
N G
NG
Jaspers
M
M
Oshimura
E J
EJ
Stanbridge
P H
PH
Lohman
M Z
MZ
Zdzienicka
D000818:Animals; D001260:Ataxia Telangiectasia / Q000235:genetics*; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D002886:Chromosomes, Human, Pair 17; D002887:Chromosomes, Human, Pair 18; D002896:Chromosomes, Human, Pair 6; D004247:DNA / Q000096:biosynthesis; D004307:Dose-Response Relationship, Radiation; D005816:Genetic Complementation Test; D006801:Humans; D006822:Hybrid Cells; D051379:Mice; D010641:Phenotype; D011836:Radiation Tolerance / Q000235:genetics; D014965:X-Rays
D004247:DNA