title: Partial loss of the DNA repair scaffolding protein, Xrcc1, results in increased brain damage and reduced recovery from ischemic stroke in mice.
abstract: Oxidative DNA damage is mainly repaired by base excision repair (BER). Previously, our laboratory showed that mice lacking the BER glycosylases 8-oxoguanine glycosylase 1 (Ogg1) or nei endonuclease VIII-like 1 (Neil1) recover more poorly from focal ischemic stroke than wild-type mice. Here, a mouse model was used to investigate whether loss of 1 of the 2 alleles of X-ray repair cross-complementing protein 1 (Xrcc1), which encodes a nonenzymatic scaffold protein required for BER, alters recovery from stroke. Ischemia and reperfusion caused higher brain damage and lower functional recovery in Xrcc1(+/-) mice than in wild-type mice. Additionally, a greater percentage of Xrcc1(+/-) mice died as a result of the stroke. Brain samples from human individuals who died of stroke and individuals who died of non-neurological causes were assayed for various steps of BER. Significant losses of thymine glycol incision, abasic endonuclease incision, and single nucleotide incorporation activities were identified, as well as lower expression of XRCC1 and NEIL1 proteins in stroke brains compared with controls. Together, these results suggest that impaired BER is a risk factor in ischemic brain injury and contributes to its recovery.
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD, USA.
authors.forename: Somnath
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD, USA.
authors.forename: Chandrika
authors.initials: C
authors.lastname: Canugovi
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD, USA.
authors.forename: Jeong Seon
authors.initials: JS
authors.lastname: Yoon
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD, USA.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Croteau
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD, USA.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD, USA. Electronic address: vbohr@nih.gov.
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
mesh_terms: D000818:Animals; D004249:DNA Damage / Q000235:genetics; D045647:DNA Glycosylases; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000172:deficiency*; D004195:Disease Models, Animal; D004720:Endonucleases; D015870:Gene Expression; D006801:Humans; D002534:Hypoxia, Brain / Q000235:genetics*; D019656:Loss of Heterozygosity / Q000235:genetics*; D008297:Male; D051379:Mice; D009711:Nucleotides; D012307:Risk Factors; D020521:Stroke / Q000235:genetics*; D013941:Thymine / Q000031:analogs & derivatives; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D004268:DNA-Binding Proteins; D009711:Nucleotides; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; C000619352:Xrcc1 protein, mouse; C029389:thymine glycol; D004720:Endonucleases; D045647:DNA Glycosylases; C481347:Neil1 protein, mouse; D013941:Thymine
keywords: Base excision repair; Oxidative stress; Stroke; Xrcc1