Computer Modeling of DNA Double-Strand Break Repair (pilot)

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Double Strand Breaks (DSBs) are the most dangerous form of DMA damage for the cell. When DSBs are not faithfully repaired they introduce chromosome aberrations (i.e. large rearrangement of the genome). Chromosome aberrations are the signature of exogenous and endogenous DMA damaging agents (e.g., free radicals from metabolic reactions, incomplete recombination events, radiation, certain chemicals) and are frequently associated with processes of carcinogenesis and cancer progression. One of the earliest responses of the eukaryotic cell to the induction of DSBs is the phosphorylation of histone H2AX molecules (denoted by y -H2AX) in the vicinity of the break. Modified histone y-H2AX is essential for efficient DSB recognition and processing and it is believed to have a key role in recruiting and assembling the DMA repair machinery. Consistent with these observations cells deficient in H2AX phosphorylation show genomic instability, tumor susceptibility and radiation hypersensitivity. The goal of this project is to develop a quantitative model that helps identify the role of histone y -H2AX in the process of recruitment of DMA repair proteins to DSBs. We will accomplish this aim by first developing a computational model of diffusion of chromatin associated proteins in the cell nucleus previous to DSB induction. This will help us estimate diffusion parameters and protein concentrations under normal conditions. Second we will estimate how diffusion properties and protein concentrations deviate from the previously estimated values after the induction of DSBs. These results will allow us to characterize different recruitment models and quantitatively identify the role of y -H2AX in protein recruitment after DSB induction. This project will be developed in close collaboration with experimental biologists. Relevance to Public Health: Quantification of repair/mis-repair reactions is essential to further understand processes of chromosome aberration formation such as those observed in carcinogenesis and cancer progression and after exposure to DMA-damaging agents. Since we are interested in processes that respond to radiation, our studies will help to better predict radiation sensitivity and cancer risks from environmental or occupational exposures, to estimate past exposures to radiation, and to improve tumor radiotherapy treatments.