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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 G(2)/M checkpoint defect of ataxia-telangiectasia cells

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Overview

authors

  • Kishi, Shuji
  • Lu, K. P.

publication date

  • March 2002

journal

  • Journal of Biological Chemistry  Journal

abstract

  • 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 G(2)/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 G(2)/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 G(2)/M checkpoint defect, and radiosensitivity and demonstrate a critical role for Pin2/TRF1 in the ATM-dependent regulation of telomeres and DNA damage response.

subject areas

  • Ataxia Telangiectasia
  • Ataxia Telangiectasia Mutated Proteins
  • Bromodeoxyuridine
  • CDC2 Protein Kinase
  • Cell Aging
  • Cell Cycle Proteins
  • Cell Line
  • DNA Damage
  • DNA-Binding Proteins
  • G2 Phase
  • Genes, Dominant
  • HeLa Cells
  • Humans
  • In Situ Hybridization, Fluorescence
  • Mitosis
  • Mutation
  • Phenotype
  • Phosphorylation
  • Protein Binding
  • Protein Serine-Threonine Kinases
  • Telomere
  • Telomeric Repeat Binding Protein 1
  • Time Factors
  • Transfection
  • Tumor Suppressor Proteins
  • beta-Galactosidase
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Identity

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M111365200

PubMed ID

  • 11744712
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Additional Document Info

start page

  • 7420

end page

  • 7429

volume

  • 277

issue

  • 9

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