Original article from STEM CELLS
miRNAs Regulate p21Waf1-Cip1 Protein Expression and the DNA Damage Response in hESCs
p53-p21-mediated regulation of the G1/S checkpoint pathway of the human cell cycle is a vital control point of proliferation, and the molecular pathways governing the G1/S transition are also known to play a key role in the DNA damage response (DDR). Human embryonic stem cells (hESCs) appear to have a unique cell cycle, with a shortened G1 phase (Becker et al)which only becomes lengthened upon differentiation (Filipczyk et al). Further, a lack of p21 protein but, importantly, not of mRNA in hESCs has suggested that p21 plays no role in the G1/S transition (Bárta et al) and therefore the “canonical” p53-p21 axis of the G1/S checkpoint pathway is described as non-functional in hESCs, becoming activated only upon differentiation (Neganova and Lako). Indeed, it has been proposed that the lack of an active p53-p21 pathway is required to prevent premature differentiation of hESCs (Maimets et al). Now, a study from the laboratory of Ales Hampl has confirmed that while p53 is active in hESCs following DNA damage, p21 protein is not produced as part of the DNA damage response (DDR). Furthermore they provide data suggesting that this is due to the actions of multiple microRNA (miRNA) families on p21 mRNA also suggesting that this mode of regulation is important in governing the G1/S transition and cell cycle checkpoint in undifferentiated hESCs (Dolezalova and Mraz et al).