Functional consequences of sequence alterations in the ATM gene.
The product of the gene (ATM) mutated in the human genetic disorder ataxia-telangiectasia (A-T) is a high molecular weight, protein ( approximately 350kDa) containing a C-terminal protein kinase domain and a number of other putative domains not yet functionally defined. The majority of ATM gene mutations in A-T patients are truncating, resulting in prematurely terminated products that are highly unstable. Missense mutations within the kinase domain and elsewhere in the molecule alter the stability of the protein and lead to loss of protein kinase activity. Only rarely are patients observed with two missense mutations and this gives rise to a milder disease phenotype. Evidence for a dominant interfering effect on normal ATM kinase activity has been reported in cell lines transfected with missense mutant ATM and in cell lines from some A-T heterozygotes. The dominant negative effect of mutant ATM is manifested by an enhancement of cellular radiosensitivity and may be responsible for the cancer predisposition observed in carriers of ATM missense mutations. In this review, we explore the domain structure of the ATM molecule, sites of interaction with other proteins and the consequences of specific amino acid changes on function.
Lavin
Martin F
MF
The Queensland Cancer Fund Research Unit, The Queensland Institute of Medical Research, P.O. Box Royal Brisbane Hospital, Herston, Brisbane 4029, Qld, Australia. martinL@qimr.edu.au
Scott
Shaun
S
Gueven
Nuri
N
Kozlov
Sergei
S
Peng
Cheng
C
Chen
Philip
P
D000595:Amino Acid Sequence; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins; D005799:Genes, Dominant; D006579:Heterozygote; D006801:Humans; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology*; D017434:Protein Structure, Tertiary; D011836:Radiation Tolerance; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases