Abstract
It has been four decades since the discovery of p53, the designated ‘Guardian of the Genome’. P53 is primarily known as a master transcription factor and critical tumor suppressor, with countless studies detailing the mechanisms by which it regulates a host of gene targets and their consequent signaling pathways. However, transcription-independent functions of p53 also strongly define its tumor-suppressive capabilities and recent findings shed light on the molecular mechanisms hinted at by earlier efforts. This review highlights the transcription-independent mechanisms by which p53 influences the cellular response to genomic instability (in the form of replication stress, centrosome homeostasis, and transposition) and cell death. We also pinpoint areas for further investigation in order to better understand the context dependency of p53 transcription-independent functions and how these are perturbed when TP53 is mutated in human cancer.
Highlights
Since its discovery 40 years ago, p53 is first and foremost known as a master transcription factor and critical tumor suppressor
Several recent studies focused on the isolation of proteins on nascent DNA under normal physiological conditions and following replication stress have identified p53 as being a component of the replisome machinery at active forks
More in vivo work is required to elucidate the circumstances under which p53 drives repair choice, downstream factors involved in Non-Homologous End Joining (NHEJ) that might interact with p53, and how these mechanisms are affected in the presence of hotspot mutants
Summary
Since its discovery 40 years ago, p53 is first and foremost known as a master transcription factor and critical tumor suppressor. Keen efforts have revealed that p53 is capable of recognizing and binding highly conserved response elements regardless of the chromatin landscape and compaction [1] This interesting feature sets it apart from transcription factors that typically act in concert through the formation of complexes. Such a mechanism of action raises the question of how the p53 transcriptional program is being regulated in a manner that allows for exquisite functions in different tissue environments, in development and disease, and in response to a variety of cellular stimuli and stresses. The degree of flux in such regulatory mechanisms and the variations in global chromatin features across cell types and physiological states can expand p53 transcription-dependent functions multifold, consistent with its association with numerous signaling pathways and cellular processes
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