Abstract
RecA protein is the prototypical recombinase. Members of the recombinase family can accurately repair double strand breaks in DNA. They also provide crucial links between pairs of sister chromatids in eukaryotic meiosis. A very broad outline of how these proteins align homologous sequences and promote DNA strand exchange has long been known, as are the crystal structures of the RecA-DNA pre- and postsynaptic complexes; however, little is known about the homology searching conformations and the details of how DNA in bacterial genomes is rapidly searched until homologous alignment is achieved. By integrating a physical model of recognition to new modeling work based on docking exploration and molecular dynamics simulation, we present a detailed structure/function model of homology recognition that reconciles extremely quick searching with the efficient and stringent formation of stable strand exchange products and which is consistent with a vast body of previously unexplained experimental results.
Highlights
Homologous genetic recombination (HR) is a prescribed and necessary part of the DNA metabolism of every freeliving organism
Recombination can accurately repair DNA double strand breaks, provides crucial links between pairs of sister chromatids in eukaryotic meiosis, and contributes in smaller ways to a host of additional cellular requirements. All of this is centered on the function of RecA-class recombinases and their capacity to catalyze (i) an alignment of homologous sequences in one single-stranded DNA and another double-stranded DNA and (ii) the transfer of one strand of DNA from the duplex to the initiating ssDNA leading to the formation of a stable heteroduplex if the ssDNA and dsDNA are homologous
We divide the overall DNA/RecA structural changes along that early process into four major conformational classes: (i) presynaptic active filament, (ii) bound B-form dsDNA, (iii) conformations with dsDNA distortions stabilized by interactions with site II, and (iv) postsynaptic filament with the complementary strand paired with the initiating strand bound to site I
Summary
Homologous genetic recombination (HR) is a prescribed and necessary part of the DNA metabolism of every freeliving organism. Recombination can accurately repair DNA double strand breaks, provides crucial links between pairs of sister chromatids in eukaryotic meiosis, and contributes in smaller ways to a host of additional cellular requirements. All of this is centered on the function of RecA-class recombinases and their capacity to catalyze (i) an alignment of homologous sequences in one single-stranded DNA (ssDNA) and another double-stranded DNA (dsDNA) and (ii) the transfer of one strand of DNA from the duplex to the initiating ssDNA leading to the formation of a stable heteroduplex if the ssDNA and dsDNA are homologous. The bound DNA strands are extended to about 1.5 times the B-form dsDNA length and present a very specific conformation, where the extension is not uniformly distributed; instead,
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