skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

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

Abstract

Inducible repair and pathway interactions may fundamentally alter the shape of dose-response curves because different mechanisms may be important under low- and high-dose exposure conditions. However, the significance of these phenomena for risk assessment purposes is an open question. This project developed new modeling tools to study the putative effects of DNA damage induction and repair on higher-level biological endpoints, including cell killing, neoplastic transformation and cancer. The project scope included (1) the development of new approaches to simulate the induction and base excision repair (BER) of DNA damage using Monte Carlo methods and (2) the integration of data from the Monte Carlo simulations with kinetic models for higher-level biological endpoints. Methods of calibrating and testing such multiscale biological simulations were developed. We also developed models to aid in the analysis and interpretation of data from experimental assays, such as the pulsed-field gel electrophoresis (PFGE) assay used to quantity the amount of DNA damage caused by ionizing radiation.

Authors:
Publication Date:
Research Org.:
Purdue University, West Lafayette, IN
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
900981
Report Number(s):
DOE/03ER63541
Purdue Reference Number 541 1338-0220; TRN: US200821%%302
DOE Contract Number:
FG02-03ER63541
Resource Type:
Technical Report
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; CELL KILLING; DNA DAMAGES; ELECTROPHORESIS; EXCISION REPAIR; INDUCTION; INSTABILITY; IONIZING RADIATIONS; KINETICS; MONTE CARLO METHOD; NEOPLASMS; REPAIR; RISK ASSESSMENT; SHAPE; TESTING; TRANSFORMATIONS; low dose; radiation biology; modeling; DNA damage; DNA repair; genomic instability; cell killing; cell transformation

Citation Formats

Stewart, Robert D. Kinetic Modeling of Damage Repair, Genome Instability, and Neoplastic Transformation. United States: N. p., 2007. Web. doi:10.2172/900981.
Stewart, Robert D. Kinetic Modeling of Damage Repair, Genome Instability, and Neoplastic Transformation. United States. doi:10.2172/900981.
Stewart, Robert D. Sat . "Kinetic Modeling of Damage Repair, Genome Instability, and Neoplastic Transformation". United States. doi:10.2172/900981. https://www.osti.gov/servlets/purl/900981.
@article{osti_900981,
title = {Kinetic Modeling of Damage Repair, Genome Instability, and Neoplastic Transformation},
author = {Stewart, Robert D},
abstractNote = {Inducible repair and pathway interactions may fundamentally alter the shape of dose-response curves because different mechanisms may be important under low- and high-dose exposure conditions. However, the significance of these phenomena for risk assessment purposes is an open question. This project developed new modeling tools to study the putative effects of DNA damage induction and repair on higher-level biological endpoints, including cell killing, neoplastic transformation and cancer. The project scope included (1) the development of new approaches to simulate the induction and base excision repair (BER) of DNA damage using Monte Carlo methods and (2) the integration of data from the Monte Carlo simulations with kinetic models for higher-level biological endpoints. Methods of calibrating and testing such multiscale biological simulations were developed. We also developed models to aid in the analysis and interpretation of data from experimental assays, such as the pulsed-field gel electrophoresis (PFGE) assay used to quantity the amount of DNA damage caused by ionizing radiation.},
doi = {10.2172/900981},
journal = {},
number = ,
volume = ,
place = {United States},
year = {Sat Mar 17 00:00:00 EDT 2007},
month = {Sat Mar 17 00:00:00 EDT 2007}
}

Technical Report:

Save / Share:
  • The incidences of neoplastic transformation induced by /sup 60/Co ..gamma..-rays in exponentially growing mouse embryo 10T1/2 cells were measured following acute and protracted exposures. Delivery of /sup 60/Co ..gamma..-rays at a low dose rate (0.1, 0.5, 2.5 rad/min) compared with a high dose rate (100 rad/min) results in appreciable, dose rate dependent reductions in cell killing and, independent of the effect on cell survival, reduces significantly the incidence of neoplastic transformation. Exposure of exponentially growing 10T1/2 cells to a dose of ..gamma..-rays in five equal daily fractions also significantly reduces transformation frequency, compared with delivery in a single dose, throughoutmore » the dose range examined (25 to 300 rads). The initial parts of the induction curves are fitted quite well by a linear dose dependence. The slopes of the regression lines for multifractionation delivery or irradiation at 0.1 rad/min, are one-third and one-half, respectively, of those for single exposures at a high dose rate. Increasing the interfraction interval up to 48 hours, or reduction of the dose per fraction further reduce incidence of neoplastic transformation. We conclude that protracted exposures of low LET radiation result in a net error-free repair of subtransformation damage.« less
  • OAK-B135 DNA Damage Recognition and Repair (DDR and R) proteins play a critical role in cellular responses to low-dose radiation and are associated with cancer. the authors have performed a systematic, genome-wide computational analysis of genomic data for human genes involved in the DDR and R process. The significant achievements of this project include: (1) Construction of the computational pipeline for searching DDR and R genes, building and validation of 3D models of proteins involved in DDR and R; (2) Functional and structural annotation of the 3D models and generation of comprehensive lists of suggested knock-out mutations; (3) Important improvementmore » of macromolecular docking technology and its application to predict the DNA-Protein complex conformation; (4) Development of a new algorithm for improved analysis of high-density oligonucleotide arrays for gene expression profiling; (5) Construction and maintenance of the DNA Damage Recognition and Repair Database; and (6) Producing 14 research papers (10 published and 4 in preparation).« less
  • DNA Damage Recognition and Repair (DDR&R) proteins play a critical role in cellular responses to low-dose radiation and are associated with cancer. We have performed a systematic, genome-wide computational analysis of genomic data for human genes involved in the DDR&R process. The significant achievements of this project include: 1) Construction of the computational pipeline for searching DDR&R genes, building and validation of 3D models of proteins involved in DDR&R; 2) Functional and structural annotation of the 3D models and generation of comprehensive lists of suggested knock-out mutations; and the development of a method to predict the effects of mutations. Largemore » scale testing of technology to identify novel small binding pockets in protein structures leading to new DDRR inhibitor strategies 3) Improvements of macromolecular docking technology (see the CAPRI 1-3 and 4-5 results) 4) Development of a new algorithm for improved analysis of high-density oligonucleotide arrays for gene expression profiling; 5) Construction and maintenance of the DNA Damage Recognition and Repair Database; 6) Producing 15 research papers (12 published and 3 in preparation).« less
  • We have examined the effect of fission-spectrum neutrons from the JANUS reactor at Argonne National Laboratory, delivered either as acute or protracted irradiation, on the incidence of neoplastic transformation in the C3H 1OT1/2 mouse embryo cell line. Acute exposures were delivered at 10 to 38 rads/min, protracted exposures at 0.086 or 0.43 rad/min. The total doses for both ranged from 2.4 to 350 rads. In the low dose region (2.4 to 80 rads), there was a large enhancement in transformation frequency when the neutrons were delivered at the low dose rates compared with the high dose rates, but the survivalmore » of the cells was not significantly different between the two exposure conditions. Analysis of the initial parts of the curves shows that the regression line for protracted doses is about 9 times steeper than that for single acute exposures. Finally, the possibility is discussed that an error-prone repair process may be causing the enhanced transformation frequency by protracted neutron exposures. 12 references, 2 figures, 1 table.« less
  • The goal of this study was to examine long-term effects of low-dose radiation exposure. One of the hypotheses was that radiation exposure would accelerate the normal aging process. The study was jointly funded by NASA and examined both low-LET radiation (╬│-rays) and high-LET radiation (1000 MeV/nucleon 56Fe ions) at doses of 0.1 Gy and up. The work used the Japanese medaka fish (Oryzias latipes), as a vertebrate model organism that can be maintained in large numbers at low cost for lifetime studies. Like other small laboratory fish, Japanese medaka share many anatomical and histological characteristics with other vertebrates, and amore » variety of genetic and genomic resources are available. Some work also used the zebrafish (Danio rerio), another widely used laboratory model organism.« less