title: p53 Pulses Diversify Target Gene Expression Dynamics in an mRNA Half-Life-Dependent Manner and Delineate Co-regulated Target Gene Subnetworks.
abstract: The transcription factor p53 responds to DNA double-strand breaks by increasing in concentration in a series of pulses of fixed amplitude, duration, and period. How p53 pulses influence the dynamics of p53 target gene expression is not understood. Here, we show that, in bulk cell populations, patterns of p53 target gene expression cluster into groups with stereotyped temporal behaviors, including pulsing and rising dynamics. These behaviors correlate statistically with the mRNA decay rates of target genes: short mRNA half-lives produce pulses of gene expression. This relationship can be recapitulated by mathematical models of p53-dependent gene expression in single cells and cell populations. Single-cell transcriptional profiling demonstrates that expression of a subset of p53 target genes is coordinated across time within single cells; p53 pulsing attenuates this coordination. These results help delineate how p53 orchestrates the complex DNA damage response and give insight into the function of pulsatile signaling pathways.
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, MSC 1500, Bethesda, MD 20892, USA.
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Porter
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, MSC 1500, Bethesda, MD 20892, USA.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Fisher
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, MSC 1500, Bethesda, MD 20892, USA. Electronic address: batchelore@mail.nih.gov.
authors.forename: Eric
authors.initials: E
authors.lastname: Batchelor
mesh_terms: D053903:DNA Breaks, Double-Stranded; D005786:Gene Expression Regulation; D006207:Half-Life; D012333:RNA, Messenger / Q000235:genetics*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53
chemical_list: D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53