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Papers In Press, published online ahead of print December 13, 2001
Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215
Corresponding Author: klu{at}caregroup.harvard.edu
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 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, et al., 2001, Telomeric protein Pin2/TRF1 as an important ATM target in response to double strand DNA breaks. 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 here 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 the 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.
J. Biol. Chem, 10.1074/jbc.M111365200
Submitted on November 28, 2001
Revised on December 13, 2001
Accepted on December 12, 2001
A critical role for Pin2/TRF1 in ATM-dependent regulation: Inhibition of Pin2/TRF1 function complements telomere shortening, the radiosensitivity and G2/M checkpoint defect of Ataxia-Telangiectasia cells
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