title: DNA damage may drive nucleosomal reorganization to facilitate damage detection.
abstract: One issue in genome maintenance is how DNA repair proteins find lesions at rates that seem to exceed diffusion-limited search rates. We propose a phenomenon where DNA damage induces nucleosomal rearrangements which move lesions to potential rendezvous points in the chromatin structure. These rendezvous points are the dyad and the linker DNA between histones, positions in the chromatin which are more likely to be accessible by repair proteins engaged in a random search. The feasibility of this mechanism is tested by considering the statistical mechanics of DNA containing a single lesion wrapped onto the nucleosome. We consider lesions which make the DNA either more flexible or more rigid by modeling the lesion as either a decrease or an increase in the bending energy. We include this energy in a partition function model of nucleosome breathing. Our results indicate that the steady state for a breathing nucleosome will most likely position the lesion at the dyad or in the linker, depending on the energy of the lesion. A role for DNA binding proteins and chromatin remodelers is suggested based on their ability to alter the mechanical properties of the DNA and DNA-histone binding, respectively. We speculate that these positions around the nucleosome potentially serve as rendezvous points where DNA lesions may be encountered by repair proteins which may be sterically hindered from searching the rest of the nucleosomal DNA. The strength of the repositioning is strongly dependent on the structural details of the DNA lesion and the wrapping and breathing of the nucleosome. A more sophisticated evaluation of this proposed mechanism will require detailed information about breathing dynamics, the structure of partially wrapped nucleosomes, and the structural properties of damaged DNA.
authors.affiliation: Department of Physics and Astronomy, University of Kansas, Lawrence, Kansas 66045, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: LeGresley
authors.affiliation: Department of Physics and Astronomy, University of Kansas, Lawrence, Kansas 66045, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Wilt
authors.affiliation: Department of Physics and Astronomy, University of Kansas, Lawrence, Kansas 66045, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Antonik
mesh_terms: D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry* / Q000235:genetics* / Q000648:ultrastructure; D004249:DNA Damage / Q000235:genetics*; D055119:Elastic Modulus; D008956:Models, Chemical; D008957:Models, Genetic; D009690:Nucleic Acid Conformation; D009707:Nucleosomes / Q000737:chemistry* / Q000235:genetics*
chemical_list: D009707:Nucleosomes; D004247:DNA