|
KMID : 0603820090150010001
|
|
Journal of Experimental & Biomedical Science
2009 Volume.15 No. 1 p.1 ~ p.8
|
|
|
Formation of DNA-Protein Crosslink at Oxidized Abasic Site Mediated by Human DNA Polymerase Iota and Mitochondrial DNA Polymerase Gamma
|
|
Son Mi-Young
Jun Hyun-Ik
Goo Sun-Young
Sung Jung-Suk
|
|
|
Abstract
|
|
|
|
Human genomic DNA is continuously attacked by oxygen radicals originated from cellular metabolic processes and numerous environmental carcinogens. 2-deoxyribonolactone (dL) is a major type of oxidized abasic (AP) lesion implicated in DNA strand scission, mutagenesis, and formation of covalent DNA-protein crosslink (DPC) with DNA polymerase (Pol) β. We show here that human DNA polymerase (Pol) ι and mitochondrial Polγ give rise to stable DNA-protein crosslink (DPC) formation that is specifically mediated by dL lesion. Polι mediates DPC formation at the incised dL residue by its 5’-deoxyribose-5-phosphate (dRP) lyase activity, while Polγ crosslinks with dL thorough its intrinsic dRP lyase and AP lyase activities. Reactivity in forming dL-mediated DPC was significantly higher with Polγ than with Polι. DPC formation by Polγ, however, can be reduced by an accessory factor of Polγ holoenzyme that may attenuate deleterious effects of crosslink adducts on mitochondrial DNA. Comparative kinetic analysis of DPC formation showed that the rate of DPC formation with either Polι or Polγ was lower than that with Polβ. These results revealed that the activity of catalytic lyase in DNA polymerases determine the efficiency of DPC formation with dL damages. Irreversible crosslink formation of such DNA polymerases by dL lesions may result in a prolonged strand scission and a suicide of DNA repair proteins, both of which could pose a threat to the genetic and structural integrity of DNA.
|
|
|
KEYWORD
|
|
|
Oxidative DNA damage, DNA repair, DNA polymerase, DNA-protein cross-link
|
|
|
FullTexts / Linksout information
|
|
|
|
|
|
Listed journal information
|
|
|