DNA end joining activity is reduced in Alzheimer's disease.
Evidence indicates that oxidative stress-induced damage to DNA, protein, and other cellular components contributes to the progression of Alzheimer's disease (AD). Several studies indicate that postmitotic neurons have a reduced capacity for some types of DNA repair, which is further compromised by aging. Thus in AD, the cellular response to increased oxidative DNA damage may be inadequate to protect the genome. Mammalian cells use several mechanisms to repair DNA damage generated during normal oxidative metabolism or by genotoxic insults. The predominant mechanism to repair double strand breaks is non-homologous end joining (NHEJ) which utilizes the DNA-dependent protein kinase (DNA-PK) complex. A cell-free DNA end joining assay was employed to determine if NHEJ was reduced in nuclear cortical extracts from brains of AD versus normal subjects. This report demonstrates that end joining activity and protein levels of DNA-PK catalytic subunit are significantly lower in AD brains compared to normal controls. The amount of end joining activity correlates with the expression of DNA-PK and is dependent on DNA-PK catalytic activity. This indicates that repair of DNA double-strand breaks by the DNA-PK-dependent NHEJ pathway may be deficient in AD.
Shackelford
Deborah A
DA
Department of Neurosciences, University of California at San Diego, La Jolla, CA 92093-0624, USA. dshackelford@uscd.edu
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology / Q000503:physiopathology*; D016022:Case-Control Studies; D002457:Cell Extracts; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology*; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology*; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016521:Electrophoresis, Gel, Pulsed-Field; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D015151:Immunoblotting / Q000379:methods; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D010957:Plasmids / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011180:Postmortem Changes; D011995:Recombination, Genetic / Q000187:drug effects / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid; D018709:Statistics, Nonparametric
C479235:2-(morpholin-4-yl)benzo(h)chromen-4-one; D002457:Cell Extracts; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D004247:DNA; D051747:DNA-Activated Protein Kinase