Physical mechanism of homology recognition and the secret of perfect match

Alexei A. Kornyshev, Imperial College London

     “Decades of research into homologous recombination have unraveled many

      of the details concerning the transfer of information between two homologous

      sequences. By contrast, the processes by which the interacting molecules

      initially co-localize are largely unknown. How can two homologous needles

      find each other in the genomic haystack?” (Barzel & Kupiec, Nature Rev, 2008)

This talk will discuss a physical mechanism of this enigma, which suggests that the structure of DNA may warrant another new function: recognition of homology.

Recombination of genes is a process in which sequences are exchanged between two DNAs. In homologous recombination fragments of the same homology are swapped. This makes possible gene shuffling between two parental copies of DNA, crucial for evolution and genetic diversity; a similar process is utilized in DNA repair, and its accuracy determines the robustness of life. It is generally accepted that understanding recombination of genes is one of the key challenges of the “post-genomic era”. The key point in homologous recombination is the swapping of correct genes: only regions with homologous sequences should be exchanged or used as a template for repair. Recombination mistakes are known to cause a variety of sever genetic diseases and contribute to aging. Fortunately, such errors are rare. The recognition of homology occurs with amazing precision, but it was established that at least 50-100 bp homology is required for it; this ensures that the fragments belong to two alleles of the same gene rather than to different genes. Still, to learn how we might assist nature in further reduction of recombination errors, diminishing their unhealthy consequences, is a challenging task. But for this we need to understand the recognition mechanism in depth.

In 2001, we suggested a simple, but nontrivial electrostatic mechanism of homology recognition of intact DNA duplexes without any assistance of proteins. This mechanism resulted from a detailed theory of the interaction of biomolecules with helical charge patterns in solutions (for review see [1]). Observation of existence of the recognition effect ,acting between intact DNA duplexes from a distance in protein-free pure electrolytic solutions, has been recently reported by the groups of T.Ohyama 2007,2013, at Waseda University; our group at Imperial, 2008, and of M. Prentiss, 2009 at Harvard (for review see [2]). 

This talk will overview the principles of the theory and discuss the existing experiments [1,2]. It will also give an update on more recent findings on the consequences of the helix-specific DNA-DNA interactions, as well as their experimental characterisation [3,4,5]. 

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[1] A.A. Kornyshev, D.J. Lee, S. Leikin, A. Wynveen Structure and interactions of biological helices. 

Rev Mod Phys 79, 943-996 (2007).

[2] A.A. Kornyshev Physics of DNA: unravelling hidden abilities encoded in the structure of 'the most important molecule’, PhysChemChemPhys 39, 12352-12378 (2010).

[3] A.A.Kornyshev, S.Leikin, Helical structure determines different susceptibilities of dsDNA, dsRNA, and tsDNA to Counterion-Induced Condensation, Biopys. J. 104, 2031-2041 (2013).

[4]  R.Cortini, A. A. Kornyshev, D. J. Lee, S. Leikin, Electrostatic braiding and homologous pairing of DNA double helices, Biophys.J.  101, 875-84 (2011); R.Cortini, D.J.Lee, A.A.Kornyshev, Chiral electrostatics breaks mirror symmetry of DNA supercoiling J.Phys.Cond.Matter14, 1850-1859 (2012).

[5]  A.A.Kornyshev, D. J. Lee, A. Wynveen, S. Leikin, Signatures of DNA flexibility, interactions and sequence-related structural variations in classical X-ray diffraction patterns, Nucleic Acids Research  39, 7289-7299 (2011).