Widespread distribution of DNA glycosylases removing oxidative DNA lesions in human and rodent brains

Abstract

High metabolic activity and low levels of antioxidant enzymes make neurons particularly prone to damage by reactive oxygen species. Thus, repair of oxidative DNA damage is essential for normal brain function. Base excision repair is the major pathway for repair of oxidative DNA damage, and is initiated by DNA glycosylases recognizing and removing the damaged base. In mammalian cells at least five different DNA glycosylases with overlapping substrate specificity, NEIL1, NEIL2, NEIL3, OGG1 and NTH1, remove oxidative DNA base lesions. Here we report mRNA expression and distribution of these five DNA glycosylases in human and rodent brains using in situ hybridization and Northern blotting supported by glycosylase activity assays. NEIL1, NEIL2, OGG1 and NTH1 showed widespread expression at all ages. In situ hybridization studies in mouse brain showed that expression of mNeil1 increased with age. In newborn mouse brain, mNeil3 revealed a discrete expression pattern in brain regions known to harbour stem cell populations, i.e., the subventricular zone, the rostral migratory stream, and the hilar region of the hippocampal formation. Expression of mNeil3 decreased with age, and in old mice brains could be detected only in layer V of neocortex. MNth1 was constitutively expressed during lifespan. In Northern blots, mOgg1 expression showed a transient decrease followed by an increase after 8 weeks of age. Assays for faPy DNA glycosylase activity revealed increased activity level with age in all brain regions analyzed. The widespread but differential expression of the DNA glycosylases recognizing oxidative base lesions suggests distinct and age dependent roles of these enzymes in genome maintenance in brain. The distribution of mNeil3 is particularly intriguing and points to a specific role of this enzyme in stem cell differentiation.

Post-hypoxic hypothermia is protective in human NT2-N neurons regardless of oxygen concentration during reoxygenation

“…and NEIL1 (Nei-like DNA glycosylase 1) 68 . Some repair ability has been reported also for NEIL3 69,70 , which is otherwise suggested to be more important for neurogenesis than for classical DNA repair [71][72][73][74] . The mechanisms for regulation of base excision repair after neuronal injury are not well understood.…”

Accumulation of 8-Oxoguanine in Liver DNA During Hyperoxic Resuscitation of Newborn Mice

“…Repair of AP sites, which are highly mutagenic and cytotoxic because DNA replication can result in either double strand breaks or misincorporations, starts with the actions of an AP endonuclease (6). DNA glycosylases show widespread but differential expression, presence, and incision activity, suggesting important age dependent roles both in brain (15) and liver tissue (16).…”

The endonuclease VIII-like proteins: new targets in the treatment of ischemic stroke?

“…[25] In the human brain, NEIL2 showed a widespread expression pattern in accordance with OGG1, NTH1, and NEIL1. [24] Rolseth et al [24] also found that NEIIL2 had a similar expression pattern as NEIL1 by detecting expression of NEIL2 in mouse brain during postnatal development, but with a slightly increased expression with age. In summary, NEIL2 has a widespread expression pattern in human and rodent and the subcellular localization of NEIL2 is in mitochondria and in the nucleus.…”

“…In the central nervous system, NEIL3 mRNA expression has been investigated in different brain areas of human adults by Northern blot hybridization. [24] NEIL3 could not be detected in any brain region of adult humans. In contrast, by studying the expression of NEIL3 in mouse brain during postnatal development, NEIL3 transcripts can be observed in the subventricular zone (SVZ), hilus of the hippocampal formation, the rostral migratory stream, and the Purkinje cell of the cerebellum in P3 mice brain.…”

“…[17][18][19] More specifically, NEIL1 was identified in all brain regions analyzed in human, and especially in the cerebellum, neocortex, and hippocampus. [24] Rolseth et al [24] showed that expression of NEIL1increases with age by in situ hybridization studies in mouse brain. Englander and Ma [25] found out that the expression of NEIL1 in the mature brain increases 1.5-2.5-fold compared to the embryonic brain.…”