Abstract
Interactions between DNA and DNA-binding proteins play an important role in many essential cellular processes. A key function of the DNA-binding protein p53 is to search for and bind to target sites incorporated in genomic DNA, which triggers transcriptional regulation. How do p53 molecules achieve “rapid” and “accurate” target search in living cells? The search dynamics of p53 were expected to include 3D diffusion in solution, 1D diffusion along DNA, and intersegmental transfer between two different DNA strands. Single-molecule fluorescence microscopy enabled the tracking of p53 molecules on DNA and the characterization of these dynamics quantitatively. Recent intensive single-molecule studies of p53 succeeded in revealing each of these search dynamics. Here, we review these studies and discuss the target search mechanisms of p53.
Highlights
Genome editing method has been used to investigate and engineer gene functions in life science
We revealed that only ~10% of p53 molecules succeed in binding to the target DNA sequence [39]
Many DNA-binding proteins bind to and cover DNA, which could block the 1D diffusion of p53 along DNA and hinder its target search
Summary
Genome editing method has been used to investigate and engineer gene functions in life science. DNA-binding proteins include enzymes, which can cut DNA or ligate two DNA molecules, and transcription factors, which can activate or deactivate gene expression These proteins are classified into DNA sequence-specific and nonspecific binders. The sequence-specific DNA-binding proteins have a common mechanism to search for and bind to their target DNA sites encoded in a genome. Successful target binding by transcription factors can trigger the regulation of the cellular functions, whereas the failure of the target search and binding is known to cause various diseases including cancers. P53 is used as a model protein because it has common features that are frequently observed in DNA-binding proteins, such as oligomerization, a disordered region, and multiple DNA-binding domains [10]. A defect in target binding by p53 causes tumorigenesis [11], indicating the importance of successful target searching and binding
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