Suppression of DNA-PK by RNAi has different quantitative effects on telomere dysfunction and mutagenesis in human lymphoblasts treated with gamma rays or HZE particles.
Basic to virtually all relevant biological effects of ionizing radiation is the underlying damage produced in DNA and the subsequent cellular processing of such damage. The damage can be qualitatively different for different kinds of radiations, and the genetics of the biological systems exposed can greatly affect damage processing and ultimate outcome--the biological effect of concern. The accurate repair of DNA double-strand breaks (DSBs) is critical for the maintenance of genomic integrity and function. Incorrect repair of such lesions results in chromosomal rearrangements and mutations that can lead to cancer and heritable defects in the progeny of irradiated parents. We have focused on the consequent phenotypic effects of faulty repair by examining connections between cellular radiosensitivity phenotypes relevant for carcinogenesis after exposure to ionizing radiation, and deficiencies in various components of the non-homologous end-joining (NHEJ) system. Here we produced deficiencies of individual components of the DNA-dependent protein kinase (DNA-PK) holoenzyme (Ku86 and the catalytic subunit, DNA-PKcs), both singly and in combination, using RNA interference (RNAi) in human lymphoblastoid cell lines. Exposure of cells exhibiting reduced protein expression to either gamma rays or 1 GeV/nucleon iron particles demonstrated differential effects on telomere dysfunction and mutation frequency as well as differential effects between radiation qualities.
Zhang
Qinming
Q
Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado 80523, USA.
Williams
Eli S
ES
Askin
Kristin F
KF
Peng
Yuanlin
Y
Bedford
Joel S
JS
Liber
Howard L
HL
Bailey
Susan M
SM
D002460:Cell Line; D003359:Cosmic Radiation / Q000009:adverse effects*; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D005720:Gamma Rays / Q000009:adverse effects*; D006801:Humans; D016296:Mutagenesis; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D034622:RNA Interference; D016615:Telomere / Q000502:physiology / Q000528:radiation effects*
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases