Kinetic Modeling of Damage Repair, Genome Instability, and Neoplastic Transformation

U.S. Department of Energy, Low Dose Radiation Research Program.  Science in Support of Radiation Risk Policy.

Co-Investigators:

E.J. Ackerman, Ph.D. Pacific Northwest National Laboratory

A. Chatterjee, Ph.D. Lawrence Berkeley National Laboratory

P.K. Cooper, Ph.D. Lawrence Berkeley National Laboratory

B.R. Scott, Ph.D. Lovelace Respiratory Research Institute.

Project Objective

Experiments have shown that cells sometimes display an adaptive response to fractionated doses of chemical and radiological agents. Transient up regulation of DNA repair provides a plausible explanation for the observed adaptations in cellular responses. The kinetics of DNA damage repair, and hence cellular responses to damage, may be further complicated by cross talk and sharing of proteins amongst various repair and transcriptional pathways and by pathway competition for the same damaged DNA substrate. The major objective of this project is to develop new modeling tools to study the putative effects that inducible repair phenomena and pathway interactions have on the shape of dose-response curves for biological endpoints relevant to the pathogenesis of cancer.

Research Approach

We have assembled a team of modelers and experimentalists with expertise in DNA repair mechanisms to perform the following specific aims:

1.  Use Monte Carlo models to estimate the fidelity of multiply damaged site (MDS) repair.  In addition to 40 double strand breaks (DSBs) Gy^-1 cell^-1, ionizing radiation also produces ~ 400 to 1,600 other kinds of multiply damaged DNA site Gy^-1 cell^-1. On theoretical grounds, multiply damaged sites other than the DSB may be responsible for as many as 20 to 80 mutations Gy^-1 cell^-1.  To better define the mutagenic potential of radiation, Monte Carlo methods will be used to simulate the base and nucleotide excision repair of DNA damage configurations representative of those formed by sparsely ionizing radiation.  Base and nucleotide excision repair are two of the main pathways responsible for the removal of multiply damaged sites other than the DSB.  Moreover, some experiments suggest that these pathways may be inducible by chemical and radiological agents.

2.  Use kinetic models to relate biochemical processing of DNA damage to the onset of genomic instability and the transformation or killing of cells.  Pathway-specific, inducible repair models based on the variants of the classic Michaelis-Menten (mass action) formalism will be developed and integrated into our existing Virtual Cell (VC) radiobiology software.  The revised software will provide a mechanism-based framework to relate biochemical processing of DSBs and other kinds of DNA damage to the neoplastic transformation and killing of cells by radiation.

3.  Conduct a preliminary study of the putative effects of pathway interactions and inducible repair phenomena.  Multi-objective optimization methods will be used to calibrate the models based on data for (1) the rate(s) of damage repair, (2) cell survival data as a function of dose and dose rate, and (3) neoplastic cell transformation as a function of dose and dose rate.  Other molecular and cellular data (e.g., initial yield of DNA damage Gy^-1 cell^-1) will be used to place biologically plausible constraints on model inputs.  Latin hypercube sampling will be used to perform an uncertainty analysis to determine the relative importance of input uncertainties in terms of their contribution to uncertainties in model outputs.  The uncertainty analyses will help identify the critical experimental inputs needed to improve future modeling of damage repair, genomic instability, and oncogenic transformation.  These studies will also provide new information to help answer questions such as

·     Is it likely that multiply damaged sites other than the DSB make a significant contribution to radiation mutagenesis and the neoplastic transformation of cells?

·     How important are inducible repair phenomena for chronic and fractionated low-dose (< 0.02 Gy) exposure conditions?

Publications

• H. Schöllnberger, R.D. Stewart, and R.E.J. Mitchel. Radioprotective mechanisms within a two-stage cancer model. In Press Nonlinearity in Biology, Toxicology and Medicine (2006).

• V.A. Semenenko and R.D. Stewart. Fast Monte Carlo simulation of DNA damage formed by electrons and light ions. Phys. Med. Biol. 51(7), 1693-1706 (2006).

• R. K. Ratnayake, V. A. Semenenko and R. D. Stewart. Retrospective analysis of DSB rejoining data collected using warm-lysis PFGE protocols. Int. J Radiat. Biol. 81(6), 421-428 (2005).

• V.A. Semenenko and R.D. Stewart. Monte Carlo Simulation of Base and Nucleotide Excision Repair of Clustered DNA Damage Sites. II. Comparisons of Model Predictions to Measured Data. Radiat. Res. 164, 194-201 (2005).

• V.A. Semenenko, R.D. Stewart, E.J. Ackerman. Monte Carlo Simulation of Base and Nucleotide Excision Repair of Clustered DNA Damage Sites. I. Model Properties and Predicted Trends. Radiat. Res. 164, 180-193 (2005).

• H. Schöllnberger, R.D. Stewart, R.E.J. Mitchel, and W. Hofmann. An examination of radiation hormesis mechanisms using a multi-stage carcinogenesis model. Nonlinearity in Biology, Toxicology and Medicine 2, 317-352 (2004).
• V.A. Semenenko and R.D. Stewart. A fast Monte Carlo algorithm to simulate the spectrum of DNA damages formed by ionizing radiation. Radiat Res. 161(4), 451-457 (2004).

• M. Guerrero, R.D. Stewart, J. Wang, and X.A. Li. Equivalence of the Linear-Quadratic and Two-Lesion Kinetic Models. Phys. Med. Biol. 47, 3197–3209 (2002).

Presentations

• R.D. Stewart, V.A. Semenenko, and R.K. Ratnayake. Fast Monte Carlo Models to Simulate the Formation and Excision Repair of DNA Damage.  Presented at the VIII^th International Workshop on Radiation Damage to DNA, M. Weinfeld and D. Murray, Chair.  Banff, Canada May 25-30, 2004.
• V.A. Semenenko, R.D. Stewart and E.J. Ackerman, Monte Carlo Simulation of the Base and Nucleotide Excision Repair of Multiply Damaged DNA Sites. Presented at the 51^st Annual Meeting of the Radiation Research Society in St. Louis, MO, April 24 - 27, 2004.
• R.D. Stewart, R.K. Ratnayake and V.A. Semenenko, DNA Repair and the Mutagenic and Cell Killing Potential of Singly and Multiply Damaged DNA Sites. Presented at the 51^st Annual Meeting of the Radiation Research Society in St. Louis, MO, April 24 - 27, 2004.
• H. Schöllnberger, R.D. Stewart, R.E.J. Mitchel, and W. Hofmann. An examination of radiation hormesis mechanisms using a multi-stage carcinogenesis model.  Presented at the 12th International Congress of Radiation Research (ICRR 2003), Brisbane Australia August 17-22 (2003).
• H. Schollnberger, M.G. Ménache, R.D. Stewart, and W. Hofmann. Impact of cellular defense mechanisms and bystander effects on a multi-stage carcinogenesis model. International Conference on Non-Linear Dose-Response Relationships in Biology, Toxicology and Medicine, University of Massachusetts, Amherst, June 2002.
• R.D. Stewart, E.J. Ackerman, X.C. Lei, B.R. Scott, and J.M. Malard.  Hierarchical modeling of DNA repair, genomic instability, bystander effects, and the transformation or killing of cells.  Submitted to the 49th Annual Meeting of the Radiation Research Society. PNNL-SA-35543 Reno Hilton Hotel. Reno, Nevada, April 20-24, 2002.
• R.D. Stewart, E.J. Ackerman, J.K. Shultis, and X.C. Lei.  Modeling Bystander Effects Using a Microdosimetric Approach.  DOE Low Dose Radiation Research Program Workshop III. PNNL-SA-3592.  Rockville, Maryland, March 25-27, 2002.
• R.D. Stewart, Virtual Cell Radiobiology Software. Invited talk. Department of Nuclear Engineering and Radiation Health Physics, Oregon State University, March 4, 2002.
• R.D. Stewart, Current Topics in Radiobiological Modeling. PNNL-SA-35325.  Invited talk.  Department of Nuclear Engineering and Radiation Health Physics, Oregon State University, October 30, 2001.

Acknowledgement

Research supported by the Low Dose Radiation Research Program, Biological and Environmental Research (BER), U.S. Department of Energy, Grant No. DE-FG02-03ER63541.

Last updated: July 22, 2006