Nature Genetics
20, 398 - 400 (1998)
doi:10.1038/3882
ATM associates with and phosphorylates p53: mapping the region of interaction
Kum Kum Khanna.1, 2, Katherine E. Keating1, Sergei Kozlov1, Shaun Scott1, Magtouf Gatei1, Karen Hobson1, Yoichi Taya3, Brian Gabrielli1, Doug Chan4, Susan P. Lees-Miller4
& Martin F. Lavin1, 51
The Queensland Institute of Medical Research, PO Royal
Brisbane Hospital, Brisbane, Qld, 4029, Australia. 2
The Department of Pathology, The University of Queensland,
PO Royal Brisbane Hospital, Brisbane, Qld,
4029, Australia. 3
National Cancer Center Research Institute,
Tsukiji 5-1-1, Chuo-ku, Tokyo 104, Japan. 4
The University of Calgary, 2500 University
Drive, N.W. Calgary, Alberta, T2N IN4, Canada. 5
The Department of Surgery, The University of Queensland,
PO Royal Brisbane Hospital, Brisbane, Qld,
4029, Australia.
Correspondence should be addressed to Kum Kum Khanna. kumkumK@qimr.edu.auThe human genetic disorder ataxia-telangiectasia (AT) is characterized
by immunodeficiency, progressive cerebellar ataxia, radiosensitivity, cell
cycle checkpoint defects and cancer predisposition1. The gene
mutated in this syndrome, ATM (for AT mutated), encodes a protein containing
a phosphatidyl-inositol 3-kinase (PI-3 kinase)-like domain2,
3.
ATM also contains a proline-rich region4 and a leucine zipper2,
5, both of which implicate this protein in signal transduction.
The proline-rich region has been shown to bind to the SH3 domain of c-Abl,
which facilitates its phosphorylation and activation by ATM (Refs 4,6). Previous results have
demonstrated that AT cells are defective in the G1/S checkpoint activated
after radiation damage and that this defect is attributable to a defective
p53 signal transduction pathway7,
8. We report here direct interaction
between ATM and p53 involving two regions in ATM, one at the amino terminus
and the other at the carboxy terminus, corresponding to the PI-3 kinase domain.
Recombinant ATM protein phosphorylates p53 on serine 15 near the N terminus.
Furthermore, ectopic expression of ATM in AT cells restores normal ionizing
radiation (IR)-induced phosphorylation of p53, whereas expression of ATM
antisense RNA in control cells abrogates the rapid IR-induced phosphorylation
of p53 on serine 15. These results demonstrate that ATM can bind p53 directly
and is responsible for its serine 15 phosphorylation, thereby contributing
to the activation and stabilization of p53 during the IR-induced DNA damage
response.
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