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J. Biol. Chem., Vol. 277, Issue 9, 7420-7429, March 1, 2002
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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.
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*
and
*
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.
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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