Partial loss of the DNA repair scaffolding protein, Xrcc1, results in increased brain damage and reduced recovery from ischemic stroke in mice

Somnath Ghosh, Chandrika Canugovi, Jeong Seon Yoon, David M. Wilson, Deborah L. Croteau, Mark P. Mattson, Vilhelm A. Bohr

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2319-2330
Number of pages12
JournalNeurobiology of Aging
Volume36
Issue number7
DOIs
StatePublished - Jul 1 2015
Externally publishedYes

Keywords

  • Base excision repair
  • Oxidative stress
  • Stroke
  • Xrcc1

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Aging
  • Developmental Biology
  • Geriatrics and Gerontology

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