Mechanisms of diffusional search for specific targets by DNA-dependent proteins

Abstract

To perform their functions, many DNA-dependent proteins have to quickly locate specific targets against the vast excess of nonspecific DNA. Although this problem was first formulated over 40 years ago, the mechanism of such search remains one of the unsolved fundamental problems in the field of protein-DNA interactions. Several complementary mechanisms have been suggested: sliding, based on one-dimensional random diffusion along the DNA contour; hopping, in which the protein "jumps" between the closely located DNA fragments; macroscopic association-dissociation of the protein-DNA complex; and intersegmental transfer. This review covers the modern state of the problem of target DNA search, theoretical descriptions, and methods of research at the macroscopic (molecule ensembles) and microscopic (individual molecules) levels. Almost all studied DNA-dependent proteins search for specific targets by combined three-dimensional diffusion and one-dimensional diffusion along the DNA contour.

Obstacles to Scanning by RNase E Govern Bacterial mRNA Lifetimes by Hindering Access to Distal Cleavage Sites

“…The possibility that nucleic-acid binding proteins might utilize passive one-dimensional diffusion to help them locate their target elements has been debated for some time (Berg et al, 1981;Halford, 2009;Mechetin and Zharkov, 2014). However, this theoretical and empirical discussion has focused predominantly on whether linear diffusion may sometimes be preferred over other search mechanisms and not on any regulatory consequences it may have.…”

Differential Scaling of Gene Expression with Cell Size May Explain Size Control in Budding Yeast

“…A second mechanism could be TF cooperativity. Once nuclear, TFs spend most of their time bound to DNA, partitioning between a small number of high-affinity sites and a large number of low-affinity sites (Bhattacherjee and Levy, 2014;Blainey et al, 2009;Halford, 2009;Hauser et al, 2016;Jen-Jacobson et al, 2000;Mahmutovic et al, 2015;Marcovitz and Levy, 2013;Marklund et al, 2013;Mechetin and Zharkov, 2014;Melero et al, 2011;Riggs et al, 1970;Slutsky et al, 2004;Zhou, 2011). Thus, the effective concentration of a TF is the amount of TF divided by the amount of DNA, with a modest adjustment for the volume of nucleoplasm.…”

Role of Static and Dynamic Obstacles in the Protein Search for Targets on DNA

“…Interactions between them control all major cellular processes involved in transfer and maintenance of genetic information, such as transcription and post-transcription modifications, translation, DNA repair, and many others. − The starting point of these processes is a protein finding and recognizing specific target sequences on DNA that triggers the following biochemical processes. The protein search has been extensively studied using a variety of experimental and theoretical techniques. − Although a significant progress in clarifying search mechanisms has been achieved, many aspects of this complex biological process still remain not well understood. , …”