Low-dose hyper-radiosensitivity: a consequence of ineffective cell cycle arrest of radiation-damaged G2-phase cells.
This review highlights the phenomenon of low-dose hyper- radiosensitivity (HRS), an effect in which cells die from excessive sensitivity to small single doses of ionizing radiation but become more resistant (per unit dose) to larger single doses. Established and new data pertaining to HRS are discussed with respect to its possible underlying molecular mechanisms. To explain HRS, a three-component model is proposed that consists of damage recognition, signal transduction and damage repair. The foundation of the model is a rapidly occurring dose-dependent pre-mitotic cell cycle checkpoint that is specific to cells irradiated in the G2phase. This checkpoint exhibits a dose expression profile that is identical to the cell survival pattern that characterizes HRS and is probably the key control element of low-dose radiosensitivity. This premise is strengthened by the recent observation coupling low- dose radiosensitivity of G2-phase cells directly to HRS. The putative role of known damage response factors such as ATM, PARP, H2AX, 53BP1 and HDAC4 is also included within the framework of the HRS model.
Marples
B
B
Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201-2013, USA. marplesb@kci.wayne.edu
Wouters
B G
BG
Collis
S J
SJ
Chalmers
A J
AJ
Joiner
M C
MC
D000222:Adaptation, Physiological / Q000528:radiation effects; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D002453:Cell Cycle / Q000235:genetics / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D004247:DNA / Q000528:radiation effects*; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D016195:G2 Phase / Q000235:genetics* / Q000528:radiation effects*; D005786:Gene Expression Regulation / Q000528:radiation effects; D006801:Humans; D008954:Models, Biological; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000235:genetics* / Q000528:radiation effects
D004247:DNA