The Mechanisms Of Premature Cellular Senescence Induced By Heavy Ion Radiation

Senescence is a state of permanent growth arrest and is a pivotal part of the antitumorigenic barrier in vivo,which is first described by Hayflick.However,some other studies proved that senescent cells could promote tumorigenesis through secretion factors.Thus,it is need to be further studied on the relationship between senescence and tumorigenesis.Understanding the molecular mechanisms of senescence could help us to develop new method for tumor treatment.Now,different evidences revealed that cellular senescence is triggered by diverse genotoxic stimuli,including telomere dysfunction,activated oncogenes,radiation treatment,reactive oxygen species,et al.All of these stimuli induced DNA damage.Thus,DNA damage response(DDR)signal might be the key trigger of cellular senescence.However,the molecular bases of the DNA damage and their contribution to cellular senescence are not completely clear.In addition,DNA damage could induce cell cycle arrested.The classical model of senescence proposed that the genotoxic stimuli treatment activated DDR pathway and ultimately activated p53/p21 pathway,then arrested cells at G1 phase,followed by senescence.However,the accumulation of tetraploid cells in senescent cells has also be reported recently,arguing against the senescent model described above.The molecular mechanisms of this tetraploid cells undergo senescence is still unknown.To explore the molecular bases of cellular senescence induced by DNA damage and the mechanisms of senescence induction of the tetraploid cells,DNA damage was induced by carbon ions,iron ions or X-rays in human melanoma 92-1 and A375 cells.We explored the relationship between DNA damage and senescence by comparing the difference of the nature and distribution of DNA damage in chromosome induced by different kinds of radiation.We also studied the molecular bases of tetraploid cells senescence by measuring senescence associated-?-galactosidase,protein levels and cell cycle progression in irradiated cells.The experimental results showed that all of carbon ions,iron ions and X-rays induced cellular senescence is dose-dependent and is a dose saturation effect.We identified that high LET heavy ions were more effective at inducing senescence than X-rays at the same dose.We also observed less efficient repair when DNA damage was induced by heavy ions compared with X-rays and most of the irreparable damage was complex damage.Our results suggest that this complex DNA damage is difficult to repair,furthermore,low LET X-rays induced telomere-associated DNA damage is also resistant to repair,thus the complex DNA damage and telomere-associated DNA damage presents as persistent DNA damage and induces persistent DDR pathway activation.The DDR signal untimately induced p21 accumulation in damaged cells.High levels of p21 expression led to senescent induction.p21 is a key factor to determine the fate of G2 arrested cells.In p21-upregulated cells,high levels of p21 induced Aurora A kinase decline,which untimately resulted in mitosis skip and senescence entry at tetraploid G1 phase.In contrast,cells without p21 expression cannot induce Aurora A kinase degradation,which led to transient G2 arrested cells enter into M phase followed by apoptosis.Together,we suggested that p21 upregulation coupled with Aurora A kinase decline is the key event in the process of senescence entry in G2 arrested cells.