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Originally published In Press as doi:10.1074/jbc.M111365200 on December 13, 2001

J. Biol. Chem., Vol. 277, Issue 9, 7420-7429, March 1, 2002
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A Critical Role for Pin2/TRF1 in ATM-dependent Regulation
INHIBITION OF Pin2/TRF1 FUNCTION COMPLEMENTS TELOMERE SHORTENING, RADIOSENSITIVITY, AND THE G2/M CHECKPOINT DEFECT OF ATAXIA-TELANGIECTASIA CELLS*

Shuji KishiDagger and Kun Ping Lu§

From the Cancer Biology Program, Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215

Cells derived from patients with the human genetic disorder ataxia-telangiectasia (A-T) display many abnormalities, including telomere shortening, premature senescence, and defects in the activation of S phase and G2/M checkpoints in response to double-strand DNA breaks induced by ionizing radiation. We have previously demonstrated that one of the ATM substrates is Pin2/TRF1, a telomeric protein that binds the potent telomerase inhibitor PinX1, negatively regulates telomere elongation, and specifically affects mitotic progression. Following DNA damage, ATM phosphorylates Pin2/TRF1 and suppresses its ability to induce abortive mitosis and apoptosis (Kishi, S., Zhou, X. Z., Nakamura, N., Ziv, Y., Khoo, C., Hill, D. E., Shiloh, Y., and Lu, K. P. (2001) J. Biol. Chem. 276, 29282-29291). However, the functional importance of Pin2/TRF1 in mediating ATM-dependent regulation remains to be established. To address this question, we directly inhibited the function of endogenous Pin2/TRF1 in A-T cells by stable expression of two different dominant-negative Pin2/TRF1 mutants and then examined their effects on telomere length and DNA damage response. Both the Pin2/TRF1 mutants increased telomere length in A-T cells, as shown in other cells. Surprisingly, both the Pin2/TRF1 mutants reduced radiosensitivity and complemented the G2/M checkpoint defect without inhibiting Cdc2 activity in A-T cells. In contrast, neither of the Pin2/TRF1 mutants corrected the S phase checkpoint defect in the same cells. These results indicate that inhibition of Pin2/TRF1 in A-T cells is able to bypass the requirement for ATM in specifically restoring telomere shortening, the G2/M checkpoint defect, and radiosensitivity and demonstrate a critical role for Pin2/TRF1 in the ATM-dependent regulation of telomeres and DNA damage response.

* This work was supported by National Institutes of Health Grants R01GM56230 and R01GM58556 (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.

Dagger Present address: Dept. of Cancer Biology, Dana-Farber Cancer Inst., and Dept. of Pathology, Harvard Medical School, 1 Jimmy Fund Way, Boston, MA 02115.

§ A Pew Scholar and Lymphoma and Leukemia Society Scholar. To whom correspondence should be addressed: Beth Israel Deaconess Medical Center, HIM 1047, 330 Brookline Ave., Boston, MA 02215. Tel.: 617-667-4143; Fax: 617-667-0610; E-mail: klu@caregroup.harvard.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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