Localization of a portion of extranuclear ATM to peroxisomes.
The gene mutated in the human genetic disorder ataxia-telangiectasia codes for a protein, ATM, the known functions of which include response to DNA damage, cell cycle control, and meiotic recombination. Consistent with these functions, ATM is predominantly present in the nucleus of proliferating cells; however, a significant proportion of the protein has also been detected outside the nucleus in cytoplasmic vesicles. To understand the possible role of extra-nuclear ATM, we initially investigated the nature of these vesicles. In this report we demonstrate that a portion of ATM co-localizes with catalase, that ATM is present in purified mouse peroxisomes, and that there are reduced levels of ATM in the post-mitochondrial membrane fraction of cells from a patient with a peroxisome biogenesis disorder. Furthermore the use of the yeast two-hybrid system demonstrated that ATM interacts directly with a protein involved in the import of proteins into the peroxisome matrix. Because peroxisomes are major sites of oxidative metabolism, we investigated catalase activity and lipid hydroperoxide levels in normal and A-T fibroblasts. Significantly decreased catalase activity and increased lipid peroxidation was observed in several A-T cell lines. The localization of ATM to peroxisomes may contribute to the pleiotropic nature of A-T.
Watters
D
D
Cancer Research Unit, Queensland Institute of Medical Research, Royal Brisbane Hospital, Herston, Brisbane, Australia, 4029. dianneW@qimr.edu.au
Kedar
P
P
Spring
K
K
Bjorkman
J
J
Chen
P
P
Gatei
M
M
Birrell
G
G
Garrone
B
B
Srinivasa
P
P
Crane
D I
DI
Lavin
M F
MF
D000595:Amino Acid Sequence; D000818:Animals; D001260:Ataxia Telangiectasia / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D064007:Ataxia Telangiectasia Mutated Proteins; D002374:Catalase / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008054:Lipid Peroxides / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D018901:Peroxisomal Disorders / Q000378:metabolism / Q000473:pathology; D020675:Peroxisomes / Q000737:chemistry*; D017346:Protein Serine-Threonine Kinases / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D025521:Tumor Suppressor Proteins; D020798:Two-Hybrid System Techniques
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D008054:Lipid Peroxides; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; D002374:Catalase; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases