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J. Biol. Chem., Vol. 276, Issue 31, 29282-29291, August 3, 2001
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From the Cancer Biology Program, Division of Hematology/Oncology,
Department of Medicine, Beth Israel Deaconess Medical Center and
Harvard Medical School, Boston, Massachusetts 02215, the
ATM mutations are
responsible for the genetic disease ataxia-telangiectasia (A-T).
ATM encodes a protein kinase that is activated by ionizing
radiation-induced double strand DNA breaks. Cells derived from A-T
patients show many abnormalities, including accelerated telomere loss
and hypersensitivity to ionizing radiation; they enter into mitosis and
apoptosis after DNA damage. Pin2 was originally identified as a protein
involved in G2/M regulation and is almost identical to
TRF1, a telomeric protein that negatively regulates telomere
elongation. Pin2 and TRF1, probably encoded by the same gene,
PIN2/TRF1, are regulated during the cell cycle.
Furthermore, up-regulation of Pin2 or TRF1 induces mitotic entry and
apoptosis, a phenotype similar to that of A-T cells after DNA damage.
These results suggest that ATM may regulate the function of Pin2/TRF1, but their exact relationship remains unknown. Here we show that Pin2/TRF1 coimmunoprecipitated with ATM, and its phosphorylation was
increased in an ATM-dependent manner by ionizing DNA
damage. Furthermore, activated ATM directly phosphorylated Pin2/TRF1
preferentially on the conserved Ser219-Gln site
in vitro and in vivo. The biological
significance of this phosphorylation is substantiated by functional
analyses of the phosphorylation site mutants. Although expression of
Pin2 and its mutants has no detectable effect on telomere length in transient transfection, a Pin2 mutant refractory to ATM phosphorylation on Ser219 potently induces mitotic entry and apoptosis and
increases radiation hypersensitivity of A-T cells. In contrast, Pin2
mutants mimicking ATM phosphorylation on Ser219 completely
fail to induce apoptosis and also reduce radiation hypersensitivity of
A-T cells. Interestingly, the phenotype of the
phosphorylation-mimicking mutants is the same as that which resulted
from inhibition of endogenous Pin2/TRF1 in A-T cells by its
dominant-negative mutants. These results demonstrate for the first time
that ATM interacts with and phosphorylates Pin2/TRF1 and suggest that
Pin2/TRF1 may be involved in the cellular response to double strand DNA breaks.
Telomeric Protein Pin2/TRF1 as an Important ATM Target
in Response to Double Strand DNA Breaks*
,, and Department of Human Genetics and Molecular Medicine,
Sackler School of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel, and § Oncogene Research Products, Cambridge,
Massachusetts 02142
*
This work was supported by National Institutes of
Health Grants NS31763 (to Y. S.) and GM56230 and GM58556 (to
K. P. L.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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