Irreversible chromosome damage accumulates rapidly in the absence of ATM kinase activity
Open accessAbstract
Mutations in the ATM kinase cause the neurodegenerative disorder ataxia telangiectasia (A-T) and affected individuals are exquisitely radiation-sensitive and cancer-prone. Cells derived from A-T individuals contain chromosome aberrations and exhibit profound cellular radiosensitivity. ATM is an apical kinase critical for the activation of cell cycle checkpoints and the induction of apoptosis in irradiated cells. However, defects in these pathways are insufficient to account for the chromosomal instability seen in A-T cells. We show here that the small molecule KU55933 can be used as a "molecular switch" to selectively and transiently inhibit ATM kinase activity in cells. We subsequently show that the cellular radiosensitization seen when ATM kinase activity is inhibited for one hour following exposure to gamma-rays, accounts for over 70% of the total cellular radiosensitization seen when ATM kinase activity is inhibited for 17 h. Finally, we show that inhibition of ATM kinase activity for one hour following exposure to irradiation doubles the number of chromosome aberrations occurring in late-S- and G(2)-, but not M-phase, cells. These observations are unexpected and suggest that irreversible chromosome damage accumulates very rapidly when ATM kinase activity is transiently inhibited following irradiation. We propose that we have revealed an essential, yet previously undescribed, role for ATM kinase in suppressing chromosomal instability.
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Transient inhibition of ATM for one hour increases chromosome aberrations after γIR.
“transient inhibition of ATM for one hour led to increased chromosome aberrations following γIR.48,49”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [48]
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- Authors
- White, J. S., Choi, S., & Bakkenist, C. J.
- Affiliations
- University of Pittsburgh (US)
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2008-05
- Volume
- 7
- Issue
- 9
- Pages
- 1277-1284
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- OpenAlex
- W2056461221
- Cited by
- 51
- References
- 0
- Citations by year
- 2021: 2 · 2018: 1 · 2017: 4 · 2016: 3 · 2015: 6 · 2014: 2 · 2013: 7 · 2012: 6
- FWCI
- 2.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cell Cycle (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Radiation Therapy and Dosimetry
- Keywords
- ATM kinase, ataxia telangiectasia, KU55933, chromosomal instability, chromosomal abnormalities, radiosensitivity, gamma irradiation, cell cycle checkpoints
- MeSH terms
- Cell Line, Cell Line, Transformed, DNA Damage, DNA-Binding Proteins, Gamma Rays, Humans, Mitosis, Mutation, Radiation Tolerance, Time Factors, Down-Regulation, G2 Phase, S Phase, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Chromosome Breakage, Tumor Suppressor Proteins, Chromosomal Instability, Ataxia Telangiectasia Mutated Proteins
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