Duplication of ATR inhibits MyoD, induces aneuploidy and eliminates radiation-induced G1 arrest.
Chromosome 3q alterations occur frequently in many types of tumours. In a genetic screen for loci present in rhabdomyosarcomas, we identified an isochromosome 3q [i(3q)], which inhibits muscle differentiation when transferred into myoblasts. The i(3q) inhibits MyoD function, resulting in a non-differentiating phenotype. Furthermore, the i(3q) induces a 'cut' phenotype, abnormal centrosome amplification, aneuploidy and loss of G1 arrest following gamma-irradiation. Testing candidate genes within this region reveals that forced expression of ataxia-telangiectasia and rad3-related (ATR) results in a phenocopy of the i(3q). Thus, genetic alteration of ATR leads to loss of differentiation as well as cell-cycle abnormalities.
Smith
L
L
Vollum Institute, Oregon Health Sciences University, Portland 97201, USA.
Liu
S J
SJ
Goodrich
L
L
Jacobson
D
D
Degnin
C
C
Bentley
N
N
Carr
A
A
Flaggs
G
G
Keegan
K
K
Hoekstra
M
M
Thayer
M J
MJ
D000782:Aneuploidy; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics*; D002455:Cell Division; D002893:Chromosomes, Human, Pair 3; D016193:G1 Phase / Q000528:radiation effects*; D006801:Humans; D018404:Isochromosomes; D005810:Multigene Family; D009132:Muscles / Q000166:cytology; D017570:MyoD Protein / Q000037:antagonists & inhibitors* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D012208:Rhabdomyosarcoma / Q000235:genetics / Q000473:pathology; D014407:Tumor Cells, Cultured
D018797:Cell Cycle Proteins; D017570:MyoD Protein; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases