Residual ataxia telangiectasia mutated protein function in cells from ataxia telangiectasia patients, with 5762ins137 and 7271T-->G mutations, showing a less severe phenotype

G. S. Stewart, J. I. Last, T. Stankovic, Neva Elizabeth Haites, Avril Kidd, P. J. Byrd, A. M. Taylor

Research output: Contribution to journalArticle

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Abstract

We have assessed several ataxia Telangiectasia mutated (ATM)-dependent functions in cells derived from ataxia telangiectasia patients, carrying either an ATM 5762ins137 splice site or a 7271T -->G missense mutation, with a less severe phenotype compared with the classical disorder. ATM kinase in vitro, from 5762ins137 cells, showed the same specific activity as ATM in normal cells, but the protein was present at low levels. In contrast, mutant ATM kinase activity in the 7271T -->G cells was only about 6% that of the activity in normal cells, although the level of mutant protein expressed was similar to normal cells. Phosphorylation of the DNA double strand break repair proteins Nbs1 and hMre11, following DNA damage, was observed in normal and 7271T -->G cells but was almost absent in both 5762ins137 and classical ataxia telangiectasia cells. The kinetics of p53 response was intermediate between normal and classical ataxia telangiectasia cells in both the 7271T -->G and 5762ins137 cells, but interestingly, c-Jun kinase activation following DNA damage was equally deficient in cell lines derived from all the ataxia telangiectasia patients. Our results indicate that levels of ATM kinase activity, but not induction of p53 or e-Jun kinase activity, in these cells correlate with the degree of neurological disorder in the patients.

Original languageEnglish
Pages (from-to)30133-30141
Number of pages8
JournalThe Journal of Biological Chemistry
Volume276
Issue number32
DOIs
Publication statusPublished - 2001

Keywords

  • NIJMEGEN BREAKAGE SYNDROME
  • DNA-DAMAGE RESPONSE
  • ATM-DEPENDENT PHOSPHORYLATION
  • CYCLE CHECKPOINT PATHWAY
  • CENTRAL-NERVOUS-SYSTEM
  • ABL TYROSINE KINASE
  • IONIZING-RADIATION
  • C-ABL
  • INDUCED APOPTOSIS
  • P53

Cite this

Residual ataxia telangiectasia mutated protein function in cells from ataxia telangiectasia patients, with 5762ins137 and 7271T-->G mutations, showing a less severe phenotype. / Stewart, G. S.; Last, J. I.; Stankovic, T.; Haites, Neva Elizabeth; Kidd, Avril; Byrd, P. J.; Taylor, A. M.

In: The Journal of Biological Chemistry, Vol. 276, No. 32, 2001, p. 30133-30141.

Research output: Contribution to journalArticle

Stewart, G. S. ; Last, J. I. ; Stankovic, T. ; Haites, Neva Elizabeth ; Kidd, Avril ; Byrd, P. J. ; Taylor, A. M. / Residual ataxia telangiectasia mutated protein function in cells from ataxia telangiectasia patients, with 5762ins137 and 7271T-->G mutations, showing a less severe phenotype. In: The Journal of Biological Chemistry. 2001 ; Vol. 276, No. 32. pp. 30133-30141.
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abstract = "We have assessed several ataxia Telangiectasia mutated (ATM)-dependent functions in cells derived from ataxia telangiectasia patients, carrying either an ATM 5762ins137 splice site or a 7271T -->G missense mutation, with a less severe phenotype compared with the classical disorder. ATM kinase in vitro, from 5762ins137 cells, showed the same specific activity as ATM in normal cells, but the protein was present at low levels. In contrast, mutant ATM kinase activity in the 7271T -->G cells was only about 6{\%} that of the activity in normal cells, although the level of mutant protein expressed was similar to normal cells. Phosphorylation of the DNA double strand break repair proteins Nbs1 and hMre11, following DNA damage, was observed in normal and 7271T -->G cells but was almost absent in both 5762ins137 and classical ataxia telangiectasia cells. The kinetics of p53 response was intermediate between normal and classical ataxia telangiectasia cells in both the 7271T -->G and 5762ins137 cells, but interestingly, c-Jun kinase activation following DNA damage was equally deficient in cell lines derived from all the ataxia telangiectasia patients. Our results indicate that levels of ATM kinase activity, but not induction of p53 or e-Jun kinase activity, in these cells correlate with the degree of neurological disorder in the patients.",
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T1 - Residual ataxia telangiectasia mutated protein function in cells from ataxia telangiectasia patients, with 5762ins137 and 7271T-->G mutations, showing a less severe phenotype

AU - Stewart, G. S.

AU - Last, J. I.

AU - Stankovic, T.

AU - Haites, Neva Elizabeth

AU - Kidd, Avril

AU - Byrd, P. J.

AU - Taylor, A. M.

PY - 2001

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N2 - We have assessed several ataxia Telangiectasia mutated (ATM)-dependent functions in cells derived from ataxia telangiectasia patients, carrying either an ATM 5762ins137 splice site or a 7271T -->G missense mutation, with a less severe phenotype compared with the classical disorder. ATM kinase in vitro, from 5762ins137 cells, showed the same specific activity as ATM in normal cells, but the protein was present at low levels. In contrast, mutant ATM kinase activity in the 7271T -->G cells was only about 6% that of the activity in normal cells, although the level of mutant protein expressed was similar to normal cells. Phosphorylation of the DNA double strand break repair proteins Nbs1 and hMre11, following DNA damage, was observed in normal and 7271T -->G cells but was almost absent in both 5762ins137 and classical ataxia telangiectasia cells. The kinetics of p53 response was intermediate between normal and classical ataxia telangiectasia cells in both the 7271T -->G and 5762ins137 cells, but interestingly, c-Jun kinase activation following DNA damage was equally deficient in cell lines derived from all the ataxia telangiectasia patients. Our results indicate that levels of ATM kinase activity, but not induction of p53 or e-Jun kinase activity, in these cells correlate with the degree of neurological disorder in the patients.

AB - We have assessed several ataxia Telangiectasia mutated (ATM)-dependent functions in cells derived from ataxia telangiectasia patients, carrying either an ATM 5762ins137 splice site or a 7271T -->G missense mutation, with a less severe phenotype compared with the classical disorder. ATM kinase in vitro, from 5762ins137 cells, showed the same specific activity as ATM in normal cells, but the protein was present at low levels. In contrast, mutant ATM kinase activity in the 7271T -->G cells was only about 6% that of the activity in normal cells, although the level of mutant protein expressed was similar to normal cells. Phosphorylation of the DNA double strand break repair proteins Nbs1 and hMre11, following DNA damage, was observed in normal and 7271T -->G cells but was almost absent in both 5762ins137 and classical ataxia telangiectasia cells. The kinetics of p53 response was intermediate between normal and classical ataxia telangiectasia cells in both the 7271T -->G and 5762ins137 cells, but interestingly, c-Jun kinase activation following DNA damage was equally deficient in cell lines derived from all the ataxia telangiectasia patients. Our results indicate that levels of ATM kinase activity, but not induction of p53 or e-Jun kinase activity, in these cells correlate with the degree of neurological disorder in the patients.

KW - NIJMEGEN BREAKAGE SYNDROME

KW - DNA-DAMAGE RESPONSE

KW - ATM-DEPENDENT PHOSPHORYLATION

KW - CYCLE CHECKPOINT PATHWAY

KW - CENTRAL-NERVOUS-SYSTEM

KW - ABL TYROSINE KINASE

KW - IONIZING-RADIATION

KW - C-ABL

KW - INDUCED APOPTOSIS

KW - P53

U2 - 10.1074/jbc.M103160200

DO - 10.1074/jbc.M103160200

M3 - Article

VL - 276

SP - 30133

EP - 30141

JO - The Journal of Biological Chemistry

JF - The Journal of Biological Chemistry

SN - 0021-9258

IS - 32

ER -