For example, different developmental outcomes may result from a relatively moderate, i.e., less than 2-fold variation, in the level of expression of POU5F1 in hESCs. REM2 is upregulated in hESCs and is necessary to maintain

survival and pluripotency of hESCs by down-regulating p53 and cyclin D1[13]. Human ES cells are distinct from somatic cells in the expression of members of the E2F family and insulin-like growth factor RB family so-called pocket proteins, such as p105 (RB1), p107 (RBL1), and p130 (RB2) that are known to control expression of genes implicated in both DNA and nucleotide metabolism[14]. Some other distinct subsets of genes are expressed at consistently higher levels in hESCs compared to normal differentiated human cells. Among these are both components of telomerase TERT and TR[15], antioxidant genes, such as SOD2 and

GPX2[15], and many DNA repair genes, such as BRCA1, MSH3, MSH6, LIG3, DMC1, FEN1, RPA3, BLM, WRN, etc.[15,16], partly explaining higher fidelity of DNA repair in hESC after genotoxic stress exposures[17,18]. Importantly, some genes encoding key proteins implicated in cell cycle control and DNA damage signaling were also observed to be more abundantly expressed in hESCs compared to IMR-90 fibroblasts. Among them are ATR, CHEK1, PCNA, PRKDC (DNA-PKcs), and others[19]. Recently, it was demonstrated that levels of BCL-2 are lower , whereas those of pro-apoptotic PUMA are higher, in hESCs compared to human somatic cells[20], which is in concert with the tendency of hESC to undergo programmed cell death under permissive conditions. Noteworthy, the hybrid sequencing technique identified that a substantial subset of 273 novel RNAs from gene loci is expressed in human pluripotent stem cells, but not in diverse fetal and adult tissues, further adding

to the differences in gene expression signatures between human pluripotent stem cells and other types of cells[21]. The unique epigenetic landscape of the former might contribute, at least in part, to those distinct transcription profiles observed in many studies[22,23]. CHANGES IN PROTEIN-CODING GENE EXPRESSION IN IRRADIATED HESCS The transcriptional responses of many types of fully differentiated somatic human cells exposed to IR have been studied by numerous labs in the past. Much less is known about how human pluripotent stem cells, such as hESCs, respond to genotoxic stresses at the level of whole genome gene expression. Studies into such GSK-3 gene expression alterations were conducted only recently; but, we still have only partial knowledge about hESCs transcriptional programs elicited by DNA damage/genotoxic stressors. Importantly, changes affecting the global gene expression networks have been strongly associated with ultimate cell fates/outcomes in human cells undergoing genotoxic stress exposures. Such perturbations are considered to be an integral part of human cell response to DNA damage-induced stress[24,25].