Nuclear accumulation and activation of p53 in embryonic stem cells after DNA damage

Abstract

Background: P53 is a key tumor suppressor protein. In response to DNA damage, p53 accumulates to high levels in differentiated cells and activates target genes that initiate cell cycle arrest and apoptosis. Since stem cells provide the proliferative cell pool within organisms, an efficient DNA damage response is crucial.

MDM4 downregulates p53 transcriptional activity and response to stress during differentiation

“…A few studies suggest that p53 is not transcriptionally active in ES cells and cannot be activated by stress 23,24 whereas others show that p53 is active and responsive to stress. 21,22,25,26 We verify that p53 is indeed active and can be activated in ES cells, which is consistent with the observation that ES cells are genetically stable even after extensive passaging in vitro. Indeed, given their pluripotent nature and self-renewing capacity, it is important that ES cells be sensitive to stress and DNA damage, in order to correct genetic mutations before they can be transmitted to daughter cells.…”

“…Previous studies of p53 activity in ES cells have included experiments using transfected or transgenic reporters. 21,22 By integrating our reporter Having established that basal p53 activity decreases as ES cells differentiate, we sought to determine the molecular mechanism controlling p53 activity in this system. As Mdm2 is a major regulator of p53, we performed western blots to determine protein levels of p53 and Mdm2.…”

Genomic Integrity of Mouse Embryonic Stem Cells

“…For instance, IR induces the nuclear translocation of p53 after 1h while after 8h all p53 had disappeared from the nucleus, to reappear again in the nucleus after 24h. In contrast, upon UV light exposure p53 remained in the nucleus up till 24h (Solozobova et al 2009). Treatment of mES cells with the antimetabolite n-phosphonacetyl-L-aspartate (PALA) leading to rNTP depletion did not induce efficient translocation of p53 to the nucleus resulting in a significant heterogeneity in PALA-treated cells (Aladjem et al 1998).…”

“…The higher amount of p53 proteins in mES cells was not due to a higher stability in the protein, however, both RNA content and RNA stability were increased compared to MEF cells. The cause of the higher p53 protein content was due to an enhanced translation of p53 in mES cells as well as a lower expression of miRNA 125a and miRNA125b in mES cells compared to differentiated cells (Solozobova et al 2010). p53 is located in the cytoplasm in undifferentiated mES cells (Solozobova et al 2009) and is translocated to the nucleus upon challenge with IR or UV. Depending on the type of genotoxic insult the temporal pattern of p53 presence in the nucleus differs.…”

DNA Repair in Embryonic Stem Cells

“…One option is via activation of the tumor suppressor protein Tp53. Upon DNA damage, the transcription factor Tp53 accumulates in the nucleus of stem cells (Lin et al, 2005;Solozobova et al, 2009). Among the promoters, to which Tp53 binds upon activation is the promoter of nanog, an important stem cell marker gene.…”