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Letters to Nature

Nature 405, 477-482 (25 May 2000) | doi:10.1038/35013089; Received 30 December 1999; Accepted 19 April 2000

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ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response

Xiaohua Wu1,2, Velvizhi Ranganathan3,4, David S. Weisman3,4, Walter F. Heine3,4, David N. Ciccone3,4, Ted B. O'Neill3,5, Kindra E. Crick1,2, Kerry A. Pierce6, William S. Lane6, Gary Rathbun3,5, David M. Livingston1,2 & David T. Weaver3,4

  1. Dana Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA
  2. Center for Blood Research, 200 Longwood Avenue, Boston, Massachusetts 02115, USA
  3. Departments of Genetics and Medicine,
  4. Department of Microbiology and Molecular Genetics and
  5. Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA
  6. Harvard Microchemistry Facility, Harvard University, Cambridge, Massachusetts 02138 , USA

Correspondence to: David M. Livingston1,2David T. Weaver3,4 Correspondence and requests for materials should be addressed to D.M.L. or T.W.

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Nijmegen breakage syndrome (NBS) is characterized by extreme radiation sensitivity, chromosomal instability and cancer1. The phenotypes are similar to those of ataxia telangiectasia mutated (ATM) disease, where there is a deficiency in a protein kinase that is activated by DNA damage, indicating that the Nbs and Atm proteins may participate in common pathways. Here we report that Nbs is specifically phosphorylated in response to gamma-radiation, ultraviolet light and exposure to hydroxyurea. Phosphorylation of Nbs mediated by gamma-radiation, but not that induced by hydroxyurea or ultraviolet light, was markedly reduced in ATM cells. In vivo, Nbs was phosphorylated on many serine residues, of which S343, S397 and S615 were phosphorylated by Atm in vitro. At least two of these sites were underphosphorylated in ATM cells. Inactivation of these serines by mutation partially abrogated Atm-dependent phosphorylation. Reconstituting NBS cells with a mutant form of Nbs that cannot be phosphorylated at selected, ATM-dependent serine residues led to a specific reduction in clonogenic survival after gamma-radiation. Thus, phosphorylation of Nbs by Atm is critical for certain responses of human cells to DNA damage.

  1. Dana Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA
  2. Center for Blood Research, 200 Longwood Avenue, Boston, Massachusetts 02115, USA
  3. Departments of Genetics and Medicine,
  4. Department of Microbiology and Molecular Genetics and
  5. Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA
  6. Harvard Microchemistry Facility, Harvard University, Cambridge, Massachusetts 02138 , USA

Correspondence to: David M. Livingston1,2David T. Weaver3,4 Correspondence and requests for materials should be addressed to D.M.L. or T.W.