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Distinct functions of Nijmegen breakage syndrome in ataxia telangiectasia mutated-dependent responses to DNA damage.

Publication ,  Journal Article
Lee, JH; Xu, B; Lee, C-H; Ahn, J-Y; Song, MS; Lee, H; Canman, CE; Lee, J-S; Kastan, MB; Lim, D-S
Published in: Mol Cancer Res
July 2003

Phosphorylation of NBS1, the product of the gene mutated in Nijmegen breakage syndrome (NBS), by ataxia telangiectasia mutated (ATM), the product of the gene mutated in ataxia telangiectasia, is required for activation of the S phase checkpoint in response to ionizing radiation (IR). However, NBS1 is also thought to play additional roles in the cellular response to DNA damage. To clarify these additional functions of NBS1, we generated NBS cell lines stably expressing various NBS1 mutants from retroviral vectors. The ATM-dependent activation of CHK2 by IR was defective in NBS cells but was restored by ectopic expression of wild-type NBS1. The defects in ATM-dependent activation of CHK2, S phase checkpoint control, IR-induced nuclear focus formation, and radiation sensitivity apparent in NBS cells were not corrected by expression of NBS1 mutants that lack an intact MRE11 binding domain, suggesting that formation of the NBS1-MRE11-RAD50 complex is required for the corresponding normal phenotypes. Expression of NBS1 proteins with mutated ATM-targeted phosphorylation sites (serines 278 or 343) did not restore S phase checkpoint control but did restore the ability of IR to activate CHK2 and to induce nuclear focus formation and normalized the radiation sensitivity of NBS cells. Expression of NBS1 containing mutations in the forkhead-associated or BRCA1 COOH terminus domains did not correct the defects in radiation sensitivity or nuclear focus formation but did restore S phase checkpoint control in NBS cells. Together, these data demonstrate that multiple functional domains of NBS1 are required for ATM-dependent activation of CHK2, nuclear focus formation, S phase checkpoint control, and cell survival after exposure to IR.

Duke Scholars

Published In

Mol Cancer Res

ISSN

1541-7786

Publication Date

July 2003

Volume

1

Issue

9

Start / End Page

674 / 681

Location

United States

Related Subject Headings

  • ras Proteins
  • Tumor Suppressor Proteins
  • Syndrome
  • Radiation, Ionizing
  • Protein Structure, Tertiary
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Oncology & Carcinogenesis
  • Nuclear Proteins
  • Mutation
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Lee, J. H., Xu, B., Lee, C.-H., Ahn, J.-Y., Song, M. S., Lee, H., … Lim, D.-S. (2003). Distinct functions of Nijmegen breakage syndrome in ataxia telangiectasia mutated-dependent responses to DNA damage. Mol Cancer Res, 1(9), 674–681.
Lee, Joo Hyeon, Bo Xu, Chang-Hun Lee, Jun-Young Ahn, Min Sup Song, Ho Lee, Christine E. Canman, Jong-Soo Lee, Michael B. Kastan, and Dae-Sik Lim. “Distinct functions of Nijmegen breakage syndrome in ataxia telangiectasia mutated-dependent responses to DNA damage.Mol Cancer Res 1, no. 9 (July 2003): 674–81.
Lee JH, Xu B, Lee C-H, Ahn J-Y, Song MS, Lee H, et al. Distinct functions of Nijmegen breakage syndrome in ataxia telangiectasia mutated-dependent responses to DNA damage. Mol Cancer Res. 2003 Jul;1(9):674–81.
Lee, Joo Hyeon, et al. “Distinct functions of Nijmegen breakage syndrome in ataxia telangiectasia mutated-dependent responses to DNA damage.Mol Cancer Res, vol. 1, no. 9, July 2003, pp. 674–81.
Lee JH, Xu B, Lee C-H, Ahn J-Y, Song MS, Lee H, Canman CE, Lee J-S, Kastan MB, Lim D-S. Distinct functions of Nijmegen breakage syndrome in ataxia telangiectasia mutated-dependent responses to DNA damage. Mol Cancer Res. 2003 Jul;1(9):674–681.

Published In

Mol Cancer Res

ISSN

1541-7786

Publication Date

July 2003

Volume

1

Issue

9

Start / End Page

674 / 681

Location

United States

Related Subject Headings

  • ras Proteins
  • Tumor Suppressor Proteins
  • Syndrome
  • Radiation, Ionizing
  • Protein Structure, Tertiary
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Oncology & Carcinogenesis
  • Nuclear Proteins
  • Mutation