title: Combined haploinsufficiency and genetic control of the G2/M checkpoint in irradiated cells.
abstract: When cells are exposed to a dose of radiation large enough to cause chromosome aberrations, they become arrested at the G(2)/M checkpoint, facilitating DNA repair. Defects in checkpoint control genes can impart radiosensitivity. Arrest kinetics were monitored in mouse embryo fibroblasts at doses ranging from 10 mGy to 5.0 Gy of γ radiation over a time course of 0 to 12 h. We observe no significant checkpoint engagement at doses below 100 mGy. The checkpoint is only fully activated at doses where most of the cells are either bound for mitotic catastrophe or are reproductively dead. Atm null cells with ablated checkpoint function exhibited no robust arrest. Surprisingly, haploinsufficiency for ATM alone or in combination with other radioresistance genes did not alter checkpoint activation. We have shown previously that haploinsufficiency for several radioresistance genes imparts intermediate phenotypes for several end points including apoptosis, transformation and survival. These findings suggest that checkpoint control does not contribute toward these intermediate phenotypes and that different biological processes can be activated at high doses compared to low doses.
authors.affiliation: Center for Radiological Research, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. efy1@columbia.edu
authors.forename: Erik F
authors.initials: EF
authors.lastname: Young
authors.forename: Lubomir B
authors.initials: LB
authors.lastname: Smilenov
authors.forename: Howard B
authors.initials: HB
authors.lastname: Lieberman
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Hall
mesh_terms: D000818:Animals; D004307:Dose-Response Relationship, Radiation; D004622:Embryo, Mammalian; D005260:Female; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism / Q000528:radiation effects*; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics* / Q000528:radiation effects*; D057895:Haploinsufficiency / Q000235:genetics*; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics* / Q000528:radiation effects*; D051379:Mice; D011247:Pregnancy