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Numerical Investigation of Sequence Dependence in Homologous Recognition: Evidence for Homology Traps

Renaud Fulconis ^*, Marie Dutreix  and Jean-Louis Viovy ^*

^* Laboratoire Physico-Chimie Curie, UMR Centre National de la Recherche Scientifique 168, and Laboratoire Génotoxicologie et Cycle Cellulaire, UMR Centre National de la Recherche Scientifique 2027, Institut Curie, Orsay, France

Correspondence: Address reprint requests to Jean-Louis Viovy, Tel.: 33-1-42-34-67-52; E-mail: jean-louis.viovy{at}curie.fr.

During the initial phase of RecA-mediated recombination, known as the search for homology, a single-stranded DNA coated by RecA protein and a homologous double-stranded DNA have to perfectly align and pair. We designed a model for the homology search between short molecules, and performed Monte Carlo Metropolis computer simulations of the process. The central features of our model are 1), the assumption that duplex DNA longitudinal thermal fluctuations are instrumental in the binding; and 2), the explicit consideration of the nucleotide sequence. According to our results, recognition undergoes a first slow nucleation step over a few basepairs, followed by a quick extension of the pairing to adjacent bases. The formation of the three-stranded complex tends to be curbed by heterologies but also by another possible obstacle: the presence of partially homologous stretches, such as mono- or polynucleotide repeats. Actually, repeated sequences are observed to trap the molecules in unproductive configurations. We investigate the dependence of the phenomenon on various energy parameters. This mechanism of homology trapping could have a strong biological relevance in the light of the genomic instability experimentally known to be triggered by repeated sequences.