Identification of the radiosensitivity gene on human chromosome 11

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Ataxia-telangiectasia(A-T)is a human recissive disease characterized by an enhanced sensitivity to ionizing radiations. The ATM gene cloned from chromosome 11q22-23 region has been assumed to be the putative A-T disease gene. In the present study the ATM gene was examined for its capability to correct A-T cellular defect by the use of a somatic cell hybrid method. A panel of radiation-reduced hybrid panel was generated from a 11/X recombinant chromosome that has a breakpoint at 11q23. As 6 hybrids had breakpoints within the 5-megabase region surrounding the ATM gene, one of them, M3.6, was used as a donor for the transfer of 11q22-23 chromosomal fragments into A-T cells. Examination of 12 hybrids that obtained a cellular radioresistance after chromosome transfer, 11 retained the chromosomal region 11S1343-11S144 where the ATM locus is located. In one exceptional clone where radioresistance was not associated with the ATM locus, a mouse chromosome fragment containing the Atm gene, the mouse homologue of human ATM gene, was found to be present in the hybrid, indicating that the ATM gene, as well as its mouse homologue Atm, has a capability to correct the cellular defect of human A-T cells. The presence of an another A-T-correcting gene localizing in 11q22-23 region outside the ATM locus was not suggested from our study. Examination of 8 A-T cell lines by restriction endonuclease fingerprinting method revealed disease-causing mutations in every cell line. Southern blot analysis of human genomic DNA using ATM cDNA as a probe revealed several hybridizing bands that are derived from the chromosomal region outside the ATM locus, suggesting the presence of ATM-related sequences which may represent a set of novel genes that are functionally related to ATM.