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FRIMEDBIO-Fri prosj.st. med.,helse,biol

Aberrant Oxidative DNA Modifications and DNA Structures in Genome Regulation

Alternative title: Oksidative DNA base modifikasjoner og DNA strukturer i genom regulering.

Awarded: NOK 6.5 mill.

DNA glycosylases are enzymes that initiate the repair of minor damage to DNA bases, which are the building blocks of our genetics. If the damaged DNA bases are not removed, they can cause cell death or mutations and eventually cancer. However, DNA glycosylases are also used in innate and adaptive immunity and are required to actively remove epigenetic markers in DNA after oxidative modification. Thus, DNA repair and epigenetics are linked processes in the cell. Although DNA repair is known to avoid the formation of mutations on DNA. Therefore, we postulate that the main function of Neil DNA glycosylases is to regulate epigenetic DNA methylation and secondary DNA structures in DNA. This is based on our unexpected findings that spontaneous mutation rates do not increase even though Neil enzymes are missing but alter gene expression and epigenetic DNA methylation, especially in connection with inflammatory responses and cognitive properties. Consistent with this, mouse models lacking Neil DNA glycosylases show clear changes in cognition and anxiety. The Neil1 DNA glycosylases have a very strong affinity for epigenetically modified bases and secondary DNA structures. This project addresses how epigenetic DNA methylation, secondary DNA structures, oxidized DNA bases and Neil enzymes work together to regulate the genomes, contributing to normal and dysfunctional cognitive and behavioral changes. Identification of fundamental processes for the regulation of epigenetics, secondary DNA structures and oxidative DNA base modifications will reveal new concepts for genome regulation, of importance to human health.

DNA glycosylases initiate base excision repair by eliminating modified bases that can cause cytotoxicity, mutations and ultimately cancer. However, DNA glycosylases are also used in innate and adaptive immunity and are required to actively remove epigenetic marks in DNA after oxidative modification. Thus, DNA repair and epigenetics use common proteins and are mechanistically linked. Although recognized for their role in mutation avoidance, we hypothesize that a major, if not the main, function of Neil DNA glycosylases and presumed “aberrant” oxidized DNA bases lies in their ability to regulate epigenetic DNA methylation and G quadruplex (G4)/intercalating motifs (i-motifs) dynamics. This is based on our unexpected findings that spontaneous mutation frequencies are not increased in Neil single, double or triple knockouts, whereas knockout of each of Neil1, 2 or 3 has distinct effects on gene expression and epigenetic DNA methylation in human cell lines and mouse organs, particularly in networks associated with neuro-inflammation, cognition and anxiety. Consistent with this, Neil knockout animals display distinct changes in cognition and anxiety. Importantly, the Ogg1 and Neil1DNA glycosylases have a very strong affinity to epigenetically modified C:C base pairs suggesting a novel non-canonical mechanism via structural recognition to epigenetically modified C:C base pairs of C-rich i-motifs. Thus, DNA glycosylases, G4/i-motif structures and epigenetic marks are mechanistically linked in genome regulation. This project address how epigenetic marks, G4 structures, i-motifs, oxidized DNA bases and Neil enzymes cooperate to dynamically regulate mammalian genomes, contributing to normal and dysfunctional cognitive and behavioral phenotypes and even neurodegeneration. Identifying the mechanisms underlying regulation of epigenetics, G4/i-motif dynamics and oxidative DNA base modifications will uncover important layers of genome regulation, with impacts on human health.

Funding scheme:

FRIMEDBIO-Fri prosj.st. med.,helse,biol