How to Relate Complex DNA Repair Genotypes to Pathway Function and, Ultimately, Health Risk

Jones, IM

Lawrence Livermore National Laboratory

关键词: Repair;    Research Programs;    Chromosomes;    Neoplasms;    Strand Breaks;   

DOI  :  10.2172/15002128
RP-ID  :  UCRL-ID-146815
RP-ID  :  W-7405-ENG-48
RP-ID  :  15002128

美国|英语

来源: UNT Digital Library

【 摘 要 】

Exposure to ionizing radiation increases the incidence of cancer. However, predicting which individuals are at most risk from radiation exposure is a distant goal. Predictive ability is needed to guide policies that regulate radiation exposure and ensure that medical treatments have maximum benefit and minimum risk. Differences between people in susceptibility to radiation are largely based on their genotype, the genes inherited from their parents. Among the important genes are those that produce proteins that repair DNA damaged by radiation. Base Excision Repair (BER) proteins repair single strand breaks and oxidized bases in DNA. Double Strand Break Repair proteins repair broken chromosomes. Using technologies and information from the Human Genome Project, we have previously determined that the DNA sequence of DNA repair genes varies within the human population. An average of 3-4 different variants were found that affect the protein for each of 37 genes studied. The average frequency of these variants is 5%. Given the many genes in each DNA repair pathway and their many variants, technical ability to determine an individual's repair genotype greatly exceeds ability to interpret the information. A long-term goal is to relate DNA repair genotypes to health risk from radiation. This study focused on the BER pathway. The BER genes are known, variants of the genes have been identified at LLNL, and LLNL had recently developed an assay for BER function using white blood cells. The goal of this initial effort was to begin developing data that could be used to test the hypothesis that many different genotypes have similar DNA repair capacity phenotypes (function). Relationships between genotype and phenotype could then be used to group genotypes with similar function and ultimately test the association of groups of genotypes with health risk from radiation. Genotypes with reduced repair function are expected to increase risk of radiation-induced health effects. The goal of this pilot project was to obtain preliminary data on genetic variation in DNA repair function in human cells that might encourage our efforts to establish a research program to relate DNA repair function to complex DNA repair genotype and ultimately to cancer risk of radiation exposure.