Abstract 2159: Oscillating p53 temporal dynamics enable proliferative recovery of cells following DNA damage

Abstract

Abstract The transcription factor and tumor suppressor protein p53 regulates cellular outcomes (e.g. cell cycle arrest, senescence or apoptosis) following DNA damage. Cellular outcomes can be influenced by modulating the temporal expression dynamics of p53, which in turn alters target gene mRNA expressions patterns. However, it is not clear how changes in such mRNA dynamics would eventually results in differences in temporal protein expression dynamics, which ultimately determines the cell outcome. By quantifying mRNA and protein by RNA-Seq and mass-spectrometry, respectively over time, we systematically categorized the different dynamics which could arise of p53 target mRNAs and proteins. We show that while p53 target proteins plateaus under pulsatile dynamics, the majority of target proteins are enhanced and accumulates under sustained dynamics including many regulators of terminal cell fates such as apoptosis and senescence. Next we derived synthesis and degradation rates based on empirical measurements to model how different p53 dynamics could lead to the assortment of subsequent target protein dynamics. We show that target protein dynamics are highly governed by protein degradation rate, implying the temporal selection of target gene expression is not pre-determined by the initiating stress signal, but rather through differences in the inherent protein degradation rates. Furthermore, we identify multiple unique signaling network motifs which results in target protein accumulation only under sustained (persistent) but not pulsatile (oscillatory) p53 dynamics. Our results highlight the diversity of mechanisms cells evolved to decode transcription factor dynamics as well as the role of p53 in governing cellular outcome, important both in understanding cellular information processing as well as therapeutic implications for cancer treatments. Citation Format: Dan Lu, Alba Jimenez, Ashwini Jambhekar, Galit Lahav. Oscillating p53 temporal dynamics enable proliferative recovery of cells following DNA damage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2159.