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Transcription factors (TFs) act as receivers and integrators of cellular signals, transmitting input information into coordinated cellular responses. They enable individual cells and, on a larger scale, tissues and organisms to adapt to changing environments. Among TFs, the tumor suppressor p53 is one of the most extensively studied due to its central role in safeguarding genome integrity in response to diverse endogenous and exogenous stresses. Aberrations in p53’s activity are associated with severe human malignancies, including cancer. The dynamics of p53 activity are both stimulus- and cell type-dependent and regulate cell fate. Following nuclear accumulation, p53 activates transcription of a wide range of target genes involved in multiple processes such as apoptosis, cell-cycle arrest, and DNA repair. Yet, the molecular mechanisms by which dynamic p53 activity is translated into distinct transcriptional outputs remain poorly understood. It is well established that transcription is not a deterministic process but rather occurs in bursts of activity and promoters switch stochastically between ON and OFF states, resulting in substantial cell-to-cell variability. In this study, I characterized how stimulus-dependent p53 dynamics are converted into specific gene regulation patterns by inducing diverse forms of DNA damage ranging from ionizing and UV radiation to clinically relevant chemotherapeutics. To quantify promoter activity at single-cell and single-molecule resolution, I employed single-molecule fluorescence in situ hybridization (smFISH) on four well-characterized p53 target genes. In collaboration, I further developed a novel Bayesian inference framework for determining kinetic parameters of stochastic gene expression from this large dataset. Using this combined theoretical and experimental approach, I revealed that features of promoter activity are differentially regulated depending on the target gene and the nature and extent of the DNA damage induced. Indeed, stimulus-specific stochastic gene expression is predominantly regulated by promoter activation and deactivation rates. Interestingly, I found that in most cases, transcriptional activity was uncoupled from the total amount of p53 and the fraction bound to DNA, highlighting that transcriptional regulation by p53 is a multi-dimensional process. Mechanistic analyses suggest that post-translational modifications (PTMs) of p53, rather than histone modifications at target promoters, might play a crucial role in shaping transcriptional outcomes. Furthermore, visualization of nascent RNA molecules revealed convergent co-transcription at selected p53 target loci, pointing to promoter architecture as an additional regulatory layer. Taken together, this work provides insights into p53-mediated transcriptional regulation as an example of a dynamic transcription factor that shapes the cellular response to DNA damage.