DUPLICATION OF ATR INHIBITS MYOD, INDUCES ANEUPLOIDY AND ELIMINATES RADIATION-INDUCED G1 ARREST

Chromosome Sq alterations occur frequently in many types of tumours. I n a genetic screen for loci present in rhabdomyosarcomas, we identifie d an isochromosome 3q [i(3q)], which inhibits muscle differentiation w hen transferred into myoblasts. The i(3q) inhibits MyoD function, resu lting in a non-differentiating phenotype. Furthermore, the i(3q) induc es a 'cut' phenotype, abnormal centrosome amplification, aneuploidy an d loss of G1 arrest following gamma-irradiation, Testing candidate gen es within this region reveals that forced expression of ataxia-telangi ectasia and rad3-related (ATR) results in a phenocopy of the i(3q). Th us, genetic alteration of ATR leads to loss of differentiation as well as cell-cycle abnormalities.