The mechanistic origin of p53 selectivity and functionalityOne of the master transcriptional regulation hubs of every human cell is the transcription factor (TF) p53 protein. p53 is activated in response to cellular stress, and is involved in the regulation of many cellular outcomes. To initiate transcription of downstream genes, p53 binds in a sequence-specific manner to many sites on the genome, called response elements (REs). Even after almost 40 years of intensive research in the field of p53, the fundamental question concerning how p53 activates its p53-dependent genes in response to the severity of the stress signal and consequently coordinates the functional outcome in a timely manner is still poorly understood. In this research, we showed that p53-dependent functional outcome groups can be differentiated by their RE flexibility. p53-dependent genes belonging to pathways activated early upon stress (e.g. DNA damage response) contain REs that are more flexible than REs of genes involved in pathways that are likely to be more strictly regulated, or that should occur at late stages in the response to stress (e.g. intrinsic apoptosis, p53 negative regulation). Moreover, based on data of chosen REs, genes that are part of outcome categories in which a response is needed immediately, timewise, have REs that are capable of transactivating the genes at a faster rate and at low levels of p53, because they are flexible. Thus, the flexibility of p53 RE contributes to the time-wise expression of p53 target genes and thereby plays a key role in cell-faith decisions in the p53 circuity. In addition, we have indications, using SELEX-seq technique, that the mechanistic source of selectivity in p53/REs interactions is encoded in the kinetic of p53/REs interactions, rather than in the thermodynamics of the interaction.
