Radiation Sensitivity and Processing of DNA Damage Following Low Doses of Gamma-Ray, Alpha Particles, and HZE Irradiation of Normal or DSB Repair Deficient Cells

Francis Cucinotta National Aeronaut & Space Administration francis.a.cucinotta@nasa.gov

Janice Pluth Lawrence Berkeley National Laboratory JMPLuth@lbl.gov

Peter O'Neill Medical Research Council p.oneill@har.mrc.ac.uk

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Why this Project?

Individual radiation sensitivity at low doses is of special relevance to DOE and NASA policy questions on the assessment of the individual's risk of carcinogenesis following radiation exposure.

Project Goals:

The major goal of this project is to further our understanding of the mechanisms of DNA double strand break (DSB) processing following low doses of low linear energy transfer (LET) radiation or high energy and charge (HZE) ions, and to apply this new knowledge towards the assessment of individual radiation sensitivity at low doses. This will be accomplished by:

1. Investigating DNA damage induction at low doses , and testing whether the subsequent mechanisms of DSB processing are different at low compared to higher doses and depend upon cell cycle.
   
   
2. Determining if the mechanisms of DSB rejoining, and temporal distributions of RIRF at low versus higher doses of a-particles are different, and if they are distinct from HZE particles of similar LET.
   
   
3. Developing a theoretical model that links models of radiation track structure, the production of simple and clustered DNA damage, and the enzymatic processes that control DNA damage processing and the cell cycle to support the understanding of our experimental studies. The objectives of the biochemical models are to relate the relevance of clustered DNA damage induced by ionizing radiation at low doses, or by a single track, to aberration/mutation induction and carcinogenesis.
   
   
4. Examining DNA damage signaling/ DNA damage recruitment of proteins during different phases of the cell cycle Using DNA DSB repair proficient and repair deficient mutant cells, to gain insights into genetic susceptibility and adaptation at low relative to higher doses in the processing of DSBs.

Experimental Approach:

Innovative new approaches will be employed to study radiation-induced repair foci (RIRF) at low doses in which less than one-track transverses the cell, and harvest the information to better understand radiation-induced carcinogenic risk and individual sensitivity. Through development of a mathematical model based on radiation track structure and biochemical kinetics to describe the stochastic and temporal distributions of RIRF and other experimental data, the hypothesis that changes in radiation induced repair and cell cycle effects are predictors of radiation sensitivity at low doses will be tested.

Expected Outcomes:

At low doses of low LET radiation (<50 mGy) interactions between DSBs within a cell are minimized so that lesion-non-lesion interactions should predominate. The relative contributions of non-homologous end joining (NHEJ) and homologous recombination (HR) differ during different phases of the cell cycle, thus cell cycle may influence significantly the DSB processing pathways utilized and the cell cycle effects induced by radiation may differ at low relative to higher doses. This research characterizing how cell cycle changes effect the determination of the pathways used in processing DSB/clustered damage at low doses, will substantially contribute to the understanding of genetic predisposition to radiation. This work will investigate the hypothesis that pathways involved in processing of radiation-induced DSBs and non-DSBs clustered damage are modulated by dose/dose rate, radiation quality, and phase of the cell cycle.