Decoding the Central Dogma: Quantitative Insights into Transcription and Translation Dynamics in the p53-Mediated DNA Damage Response.

Abstract

The central dogma describes the flow of genetic information from DNA to RNA and then to protein, a process regulated at multiple steps with the potential for reverse information flow. DNA damage, caused by external factors like radiation or internal processes, poses a threat to genomic stability and necessitates a robust DNA damage response (DDR). The tumor suppressor protein p53 is a pivotal component of the DDR, orchestrating gene expression to repair DNA, halt the growth of damaged cells or trigger cell death. Here, we discuss various quantitative methods that enabled new insights into p53 regulation of transcription and translation dynamics in response to DNA damage. Imaging techniques, such as live-cell fluorescence microscopy, have enabled the visualization of both p53 and the mRNA and protein levels of its key targets, such as MDM2, a negative regulator of p53; and p21, a key regulator of the cell cycle. Singe-cell live imaging of p53 in response to various DNA damaging agents, and in combination with inhibitors of its key regulators, suggested p53 dynamics as an important mechanism controlling cell fate and enabled the development of quantitative models for the control of p53 levels. Omics approaches complement imaging by offering comprehensive, quantitative insights into mRNA and protein changes following DNA damage. Mathematical models connect p53 dynamics with target gene regulation, revealing complexities in transcription-translation relationships. Integrating these methods can elucidate DDR intricacies at the single-cell level, enhancing our understanding of p53's role in regulating gene expression and cell fate determination.