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Fox Chase Cancer Center, Philadelphia, Pennsylvania 19027
Ataxia telangiectasia-mutated gene (ATM) is a 350-kDa
protein whose function is defective in the autosomal recessive disorder ataxia telangiectasia (AT). Affinity-purified polyclonal antibodies were used to characterize ATM. Steady-state levels of ATM protein varied from undetectable in most AT cell lines to highly expressed in
HeLa, U2OS, and normal human fibroblasts. Subcellular fractionation showed that ATM is predominantly a nuclear protein associated with the
chromatin and nuclear matrix. ATM protein levels remained constant
throughout the cell cycle and did not change in response to serum
stimulation. Ionizing radiation had no significant effect on either the
expression or distribution of ATM. ATM immunoprecipitates from HeLa
cells and the human DNA-dependent protein kinase null cell line MO59J,
but not from AT cells, phosphorylated the 34-kDa subunit of replication
protein A (RPA) complex in a single-stranded and linear double-stranded
DNA-dependent manner. Phosphorylation of p34 RPA occurred on threonine
and serine residues. Phosphopeptide analysis demonstrates that the
ATM-associated protein kinase phosphorylates p34 RPA on similar
residues observed in vivo. The DNA-dependent protein kinase activity
observed for ATM immunocomplexes, along with the association of ATM
with chromatin, suggests that DNA damage can induce ATM or a stably
associated protein kinase to phosphorylate proteins in the DNA damage
response pathway.
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G. S. Stewart, J. I. K. Last, T. Stankovic, N. Haites, A. M. J. Kidd, P. J. Byrd, and A. M. R. Taylor Residual Ataxia Telangiectasia Mutated Protein Function in Cells from Ataxia Telangiectasia Patients, with 5762ins137 and 7271Tright-arrowG Mutations, Showing a Less Severe Phenotype J. Biol. Chem., August 3, 2001; 276(32): 30133 - 30141. [Abstract] [Full Text] [PDF]
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