Increased postischemic brain injury in mice deficient in uracil-DNA glycosylase.
Uracil-DNA glycosylase (UNG) is involved in base excision repair of aberrant uracil residues in nuclear and mitochondrial DNA. Ung knockout mice generated by gene targeting are viable, fertile, and phenotypically normal and have regular mutation rates. However, when exposed to a nitric oxide donor, Ung(-/-) fibroblasts show an increase in the uracil/cytosine ratio in the genome and augmented cell death. After combined oxygen-glucose deprivation, Ung(-/-) primary cortical neurons have increased vulnerability to cell death, which is associated with early mitochondrial dysfunction. In vivo, UNG expression and activity are low in brains of naive WT mice but increase significantly after reversible middle cerebral artery occlusion and reperfusion. Moreover, major increases in infarct size are observed in Ung(-/-) mice compared with littermate control mice. In conclusion, our results provide compelling evidence that UNG is of major importance for tissue repair after brain ischemia.
Endres
Matthias
M
Department of Neurology, Charité, Humboldt University of Berlin, Berlin, Germany. matthias.endres@charite.de
Biniszkiewicz
Detlev
D
Sobol
Robert W
RW
Harms
Christoph
C
Ahmadi
Michael
M
Lipski
Andreas
A
Katchanov
Juri
J
Mergenthaler
Philipp
P
Dirnagl
Ulrich
U
Wilson
Samuel H
SH
Meisel
Andreas
A
Jaenisch
Rudolf
R
D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000033:anatomy & histology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000378:metabolism; D009599:Nitroprusside / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution; D051981:Uracil-DNA Glycosidase
D020030:Nitric Oxide Donors; D009599:Nitroprusside; D045647:DNA Glycosylases; D051981:Uracil-DNA Glycosidase; D005947:Glucose; D010100:Oxygen