DNA dynamicsdictates p53 functional outcome
Tali E. Haran
Abstract
The tumor suppressor protein p53 issituated in the midst of a complex cellular network that is activated inresponse to cellular stress. Activated p53 functions mainly as a transcriptionfactor, regulating the expression of numerous genes involve in various cellularpathways critical for preventing cancer, and in pathways unrelated to cancersurveillance. An unresolved question in the field is how p53 is able to parseits myriad functions in response to the severity of the stress signal andconsequently to coordinate the functional outcome in a timely manner. We havepreviously shown that DNA torsional flexibility distinguishes between differentp53 response elements (REs). I will show that across the genome p53 targetgenes belonging to pathways acting early in the stress response (e.g., DNAdamage response and innate immunity) have REs that are significantly moreflexible than REs of genes involved in pathways that need to be more strictlyregulated, or that their functional outcome occurs later in the response tostress (e.g., intrinsic apoptosis and p53 negative regulation). We validatedthese statistical findings by several complementary experimental approaches, invitro and in cells, for six p53 REs belonging to pathways that operate atdifferent times post p53 induction. Our results clearly demonstrate that theflexibility of p53 REs contributes significantly to the temporal expression ofp53 target genes and thereby to life versus death decisions in the p53 system.
