Which way up? Recognition of homologous DNA segments in parallel and antiparallel alignments

Abstract

Homologous gene shuffling between DNA molecules promotes genetic diversity and is an important pathway for DNA repair. For this to occur, homologous genes need to find and recognize each other. However, despite its central role in homologous recombination, the mechanism of homology recognition has remained an unsolved puzzle of molecular biology. While specific proteins are known to play a role at later stages of recombination, an initial coarse grained recognition step has, however, been proposed. This relies on the sequence dependence of the DNA structural parameters, such as twist and rise, mediated by intermolecular interactions, in particular, electrostatic ones. In this proposed mechanism, sequences that have the same base pair text, or are homologous, have lower interaction energy than those sequences with uncorrelated base pair texts. The difference between the two energies is termed the "recognition energy." Here, we probe how the recognition energy changes when one DNA fragment slides past another, and consider, for the first time, homologous sequences in antiparallel alignment. This dependence on sliding is termed the "recognition well." We find there is a recognition well for anti-parallel, homologous DNA tracts, but only a very shallow one, so that their interaction will differ little from the interaction between two nonhomologous tracts. This fact may be utilized in single molecule experiments specially targeted to test the theory. As well as this, we test previous theoretical approximations in calculating the recognition well for parallel molecules against MC simulations and consider more rigorously the optimization of the orientations of the fragments about their long axes upon calculating these recognition energies. The more rigorous treatment affects the recognition energy a little, when the molecules are considered rigid. When torsional flexibility of the DNA molecules is introduced, we find excellent agreement between the analytical approximation and simulations. C 2015 AIP Publishing LLC. [http://dx

Recombination-independent recognition of DNA homology for repeat-induced point mutation

“…Our results (Gladyshev and Kleckner 2014, 2016) appear to exclude models involving G-quartets (Sen and Gilbert 1988) and DNA triplexes (Sakamoto et al 1999) that require specific nucleotide sequences, such as poly-G and polypurine/polypyrimidine tracts, respectively. Our results also exclude the electrostatic zipper model (Kornyshev and Leikin 2001), in which pairing of homologous double-stranded DNA molecules is based on their mutual electrostatic complementarity that cannot be achieved by the partially homologous sequences that still promote RIP (O’Lee et al 2015, 2016). …”

Theory of phase segregation in DNA assemblies containing two different base-pair sequence types

“…Another, less trivial effect is torsional adaptation where the helical structure of the molecules adjusts to facilitate better helix dependent interactions, due to the elasticity of the molecule [23,24]. This effect on the pair interaction was studied in [16,[25][26][27]). Including these effects in molecular assemblies is mathematically and computationally involved for finite length molecules [28].…”

“…This difference, referred to as the 'recognition energy', was first calculated in [14]. The theory of homology recognition was then developed with a higher level of sophistication in a series of subsequent works (for review see [10,15], and for a recent study [16] with citations to later articles contained therein). The recognition energy can comprise several k T B per persistence length, and it increases with the length of the molecules.…”

“…Later works have suggested that the preferred conformation of DNA with the same sequence will be parallel (i.e. parallel alignment with base pair sequences running in the same direction) to each other but not antiparallel (parallel alignment but base pair sequences in opposite directions), as this recognition depends on the homologous sequences being in face-to-face register, with base pairs of the same type for the two molecules being directly across from each other [16].…”

Protein/DNA interactions in complex DNA topologies: expect the unexpected

“…Condensation of DNA (Teif and Bohinc 2011) has also been shown to require specific DNA–ion bridging interactions, which may be highly dependent on the helical repeat as the recognition between two DNA segments with similar helical twists and/or groove sizes should be preferable (Kornyshev and Leikin 2013). This has been hypothesised to drive the recombination of homologous DNA, which is crucial for gene shuffling and DNA repair (Lee et al 2015). …”