Simplified biased random walk model for RecA-protein-mediated homology recognition offers rapid and accurate self-assembly of long linear arrays of binding sites

Kates‐Harbeck, Julian; Tilloy, Antoine; Prentiss, Mara

doi:10.1103/physreve.88.012702

Cited by 19 publications

(32 citation statements)

References 29 publications

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“…Interestingly, previous theoretical studies have suggested that the net change in binding free energy for each correctly paired triplet should be on the order of thermal energy (42)(43)(44) and that the fidelity of base triplet pairing during DNA strand exchange would benefit from relatively low changes in binding free energy for each triplet step (42)(43)(44). These studies have also suggested that the structural deformation necessary to extend B-DNA to match the much longer extension of RS-DNA may enhance the ability of the presynaptic complex to reject nonhomologous sequences during the homology search (44 -46).…”

Section: Discussionmentioning

confidence: 99%

ATP hydrolysis Promotes Duplex DNA Release by the RecA Presynaptic Complex

Lee

Greene

2016

Journal of Biological Chemistry

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Homologous recombination is an important DNA repair pathway that plays key roles in maintaining genome stability. Escherichia coli RecA is an ATP-dependent DNA-binding protein that catalyzes the DNA strand exchange reactions in homologous recombination. RecA assembles into long helical filaments on single-stranded DNA, and these presynaptic complexes are responsible for locating and pairing with a homologous duplex DNA. Recent single molecule studies have provided new insights into RecA behavior, but the potential influence of ATP in the reactions remains poorly understood. Here we examine how ATP influences the ability of the RecA presynaptic complex to interact with homologous dsDNA. We demonstrate that over short time regimes, RecA presynaptic complexes sample heterologous dsDNA similarly in the presence of either ATP or ATP␥S, suggesting that initial interactions do not depend on ATP hydrolysis. In addition, RecA stabilizes pairing intermediates in three-base steps, and stepping energetics is seemingly unaltered in the presence of ATP. However, the overall dissociation rate of these paired intermediates with ATP is ϳ4-fold higher than with ATP␥S. These experiments suggest that ATP plays an unanticipated role in promoting the turnover of captured duplex DNA intermediates as RecA attempts to align homologous sequences during the early stages of recombination.Homologous recombination allows for the regulated exchange of genetic information between two different DNA molecules of identical or nearly identical sequence composition (1-4). Homologous recombination contributes to double-strand DNA break repair, the rescue of stalled or collapsed replication forks, programmed and aberrant chromosomal rearrangements, horizontal gene transfer, and meiosis (5-9). The importance of homologous recombination is underscored by its broad conservation across all kingdoms of life and the findings that defects in key recombination proteins can result in a loss of genome integrity and lead to gross chromosomal rearrangements that are a hallmark of cancer in eukaryotes.Many of the key reactions in homologous recombination are catalyzed by the Rad51/RecA family of DNA recombinases (1-4). These recombinases are broadly conserved, and prominent family members include bacterial RecA, the archeal protein RadA, and the eukaryotic recombinases Rad51 and Dmc1. RecA is the archetypal recombinase originally identified in genetic screens for Escherichia coli mutants defective in recombination (10), and much of our current understanding of recombination mechanisms can be attributed to studies of bacterial RecA (4).During recombination, RecA bound to the presynaptic ssDNA must first locate a homologous duplex DNA template. This process is referred to as the homology search, and it is conceptually similar to the target searches of other site-specific DNA-binding proteins (11)(12)(13)(14). Once aligned, the presynaptic ssDNA can be paired with the complementary strand of a homologous dsDNA, resulting in the displacement of the noncomplementary s...

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Section: Discussionmentioning

confidence: 99%

ATP hydrolysis Promotes Duplex DNA Release by the RecA Presynaptic Complex

Lee

Greene

2016

Journal of Biological Chemistry

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“…If the first ~9 bases in C have all flipped and paired with I, the strand exchange product becomes metastable [20,28] and homology recognition proceeds much more slowly as an iterative search in units of successive bp triplets [29]. The latter process can be modeled as a biased random walk (BRW) [30]. We will refer to the initial sequence-independent stage as pre-BRW.…”

Section: Modelmentioning

confidence: 99%

RecA-mediated sequence homology recognition as an example of how searching speed in self-assembly systems can be optimized by balancing entropic and enthalpic barriers

Jiang

Prentiss

2014

Phys. Rev. E

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Ideally, self-assembly should rapidly and efficiently produce stable correctly assembled structures. We study the tradeoff between enthalpic and entropic cost in self-assembling systems using RecA-mediated homology search as an example. Earlier work suggested that RecA searches could produce stable final structures with high stringency using a slow testing process that follows an initial rapid search of ~9–15 bases. In this work, we will show that as a result of entropic and enthalpic barriers, simultaneously testing all ~9–15 bases as separate individual units results in a longer overall searching time than testing them in groups and stages.

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“…The importance of length-dependent sequence recognition as a means for rapidly rejecting incorrect sequences was first recognized by Charles Thomas, Jr. (60), who in 1966 suggested that it would be beneficial for recombination to take place between nonrepetitive minimal recognition lengths composed of "words" that can be uniquely identified within the genome, and these original concepts have been further elaborated by several groups (55,(61)(62)(63). Simply put, longer sequences are less common than shorter sequences, so there is a benefit to search for these longer sequences, which will also have a higher probability of being the correct homologous target (Fig.…”

Section: Theoretical Considerationsmentioning

confidence: 99%

DNA Sequence Alignment during Homologous Recombination

Greene

2016

Journal of Biological Chemistry

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Homologous recombination allows for the regulated exchange of genetic information between two different DNA molecules of identical or nearly identical sequence composition, and is a major pathway for the repair of double-stranded DNA breaks. A key facet of homologous recombination is the ability of recombination proteins to perfectly align the damaged DNA with homologous sequence located elsewhere in the genome. This reaction is referred to as the homology search and is akin to the target searches conducted by many different DNA-binding proteins. Here I briefly highlight early investigations into the homology search mechanism, and then describe more recent research. Based on these studies, I summarize a model that includes a combination of intersegmental transfer, short-distance one-dimensional sliding, and length-specific microhomology recognition to efficiently align DNA sequences during the homology search. I also suggest some future directions to help further our understanding of the homology search. Where appropriate, I direct the reader to other recent reviews describing various issues related to homologous recombination. Homologous RecombinationHomologous recombination enables the exchange of genetic information between different DNA molecules and is a major driving force in evolution. Homologous recombination contributes to double-strand DNA break (DSB) 2 repair, the rescue of stalled or collapsed replication forks, programmed and aberrant chromosomal rearrangements, horizontal gene transfer, and meiosis (1-5). The importance of homologous recombination is underscored by the findings that defects in key recombination proteins can result in a loss of genome integrity and lead to gross chromosomal rearrangements that are a hallmark of cancer. During recombination, a presynaptic ssDNA is paired with the complementary strand of a homologous dsDNA, resulting in the displacement of the noncomplementary strand from the duplex to generate a D-loop intermediate ( Fig. 1) (6 -8). This intermediate can be channeled through a number of alternative pathways, any of which can allow for the repair of the originally broken DNA molecule using information derived from the template (1, 9, 10).Key reactions in homologous recombination are catalyzed by the Rad51/RecA family DNA recombinases, which are ATP-dependent proteins that form helical filaments on DNA (6 -8, 11). These recombinases are broadly conserved, and prominent family members include bacterial RecA, the archaeal protein RadA, and the eukaryotic recombinases Rad51 and Dmc1. RecA is the archetypal recombinase originally identified in genetic screens for Escherichia coli mutants defective in recombination by Clark and Margulies in 1965 (12). This discovery set the stage for years of investigation into the RecA protein, including its biochemical purification and characterization by the Radding, Howard-Flanders, Lehman, and Roberts laboratories (13)(14)(15)(16)(17)(18)(19)(20).The importance of this early work on bacterial recombination was underscored by studies in...

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Simplified biased random walk model for RecA-protein-mediated homology recognition offers rapid and accurate self-assembly of long linear arrays of binding sites

Cited by 19 publications

References 29 publications

ATP hydrolysis Promotes Duplex DNA Release by the RecA Presynaptic Complex

ATP hydrolysis Promotes Duplex DNA Release by the RecA Presynaptic Complex

RecA-mediated sequence homology recognition as an example of how searching speed in self-assembly systems can be optimized by balancing entropic and enthalpic barriers

DNA Sequence Alignment during Homologous Recombination

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