Abstract
It is well established that ionizing radiation causes cell death, however, its mechanism has not been fully understood yet. We have reported that non-apoptotic cell death is the major cause of cell death induced by radiation, particularly in attached cells. In normal human diploid cells, residual DNA double-strand breaks persistently activate ATM-dependent G1 checkpoint, thereby persistent G1 arrest leads to senescence-like growth arrest (SLGA). SLGA is also detectable in human cancer cells. Since G1 checkpoint is abrogated in most cancer cases, cells proceed to G2 phase with DNA damage. In addition, G2 arrest is prematurely abandoned in cancer cells, so that cells go into mitosis with DNA damage. As a result, cells initiate division with fragmented chromosomes and chromosome bridges, which result in abnormal mitosis, called mitotic catastrophe. These cells could not accomplish cell division and form multiple micronucleated cells in the next G1 phase. Other cells, which do not show cell division, also stay in G1 phase. We found that these cells stayed in G1 phase induced SLGA. Thus, it become evident that SLGA is induced by ionizing radiation, irrespective of activation of cell cycle checkpoint. In most tissues, SLGA is the major mode of cell death induced by radiation, and therefore, to understand its mechanism could contribute to improve the efficacy of radiotherapy.
