Biology subjects

Sakshaug, T.

Publications and source records attributed to Sakshaug, T..

3 recordsLinked to original sources

bioRxiv2024

DNA glycosylases Ogg1 and Mutyh mediate gene expression of PRC2 target genes important for neuronal processes underlying memory formation

Base excision repair (BER) initiated by DNA glycosylases is known to preserve genomic integrity by removing damaged bases. Recently, several DNA glycosylases were identified as potential readers of epigenetic modifications and proteins involved in BER have been associated with active DNA demethylation. DNA glycosylases Ogg1 and Mutyh were shown to alter the hippocampal transcriptome associated with cognitive function and independent of global DNA damage accumulation. However, the mechanism of DNA glycosylases in regulating cognition and their role in epigenetic remodeling in the brain remains elusive. Here we report that the combined deficiency of Ogg1 and Mutyh impairs spatial but not associative long-term memory. We demonstrate that Ogg1 or Mutyh modulate DNA methylation at gene regulatory regions of polycomb repressive complex 2 (PRC2) target genes in the adult hippocampus. Moreover, we find that the distribution of the PRC2 complex and histone modifications associated with PRC2 activity changes in both hippocampal neurons and glia depend on Ogg1 and Mutyh. Epigenetic alterations correlated with cell-type specific gene expression changes which were associated with pathways important for neuronal function and cognition. Our results provide a novel role for Ogg1 and Mutyh beyond DNA repair in modulating the epigenome to control transcriptional responses in the brain important for memory formation.

neuroscience↗

bioRxiv2024

Genomic 8-oxoguanine modulates gene transcription independent of its repair by DNA glycosylases OGG1 and MUTYH

8-oxo-7,8-dihydroguanine (OG) is one of the most abundant oxidative lesions in the genome and associated with genome instability. Its mutagenic potential is counteracted by a concerted action of 8-oxoguanine DNA glycosylase (OGG1) and mutY homolog DNA glycosylase (MUTYH). It has been suggested that OG and its repair has epigenetic-like properties and mediates transcription, but genome-wide evidence of this interdependence is lacking. Here, we applied an improved OG-sequencing approach reducing artificial background oxidation and RNA-sequencing to correlate genome-wide distribution of OG with gene transcription in OGG1 and/or MUTYH-deficient cells. Our data identified moderate enrichment of OG in the genome that is mainly dependent on the genomic context and not affected by DNA glycosylase-initiated repair. Interestingly, no association was found between genomic OG deposition and gene expression changes upon loss of OGG1 and MUTYH. Regardless of DNA glycosylase activity, OG in promoter regions correlated with expression of genes related to metabolic processes and damage response pathways indicating that OG functions as a cellular stress sensor to regulate transcription. Our work provides novel insights into the mechanism underlying transcriptional regulation by OG and DNA glycosylases OGG1 and MUTYH and suggests that oxidative DNA damage accumulation and its repair utilize different pathways.

genomics↗

bioRxiv2022

Age- and sex-dependent effects of DNA glycosylase Neil3 on amyloid pathology, adult neurogenesis, and memory in a mouse model of Alzheimer's disease

Oxidative stress generating DNA damage has been shown to be a key characteristic in Alzheimers disease (AD). However, how it affects the pathogenesis of AD is not yet fully understood. Neil3 is a DNA glycosylase initiating repair of oxidative DNA base lesions and with a distinct expression pattern in proliferating cells. In brain, its function has been linked to hippocampal-dependent memory and to induction of neurogenesis after stroke and in prion disease. Here, we generated a novel AD mouse model deficient for Neil3 to study the impact of impaired oxidative base lesion repair on the pathogenesis of AD. Our results demonstrate an age-dependent decrease in amyloid-{beta} (A{beta}) plaque deposition in female Neil3-deficient AD mice, whereas no significant difference was observed in male mice. Furthermore, male but not female Neil3-deficient AD mice show reduced neural stem cell proliferation in the adult hippocampus and impaired working memory compared to controls. These effects seem to be independent of DNA repair as both sexes show increased level of oxidative base lesions in the hippocampus upon loss of Neil3. Thus, our findings suggest an age- and sex-dependent role of Neil3 in the progression of AD by altering cerebral A{beta} accumulation and promoting adult hippocampal neurogenesis to maintain cognitive function.

neuroscience↗