A matter of concern - Trace element dyshomeostasis and genomic stability in neurons

Abstract

Neurons are post-mitotic cells in the brain and their integrity is of central importance to avoid neurodegeneration. Yet, the inability of self-replenishment of post-mitotic cells results in the need to withstand challenges from numerous stressors during life. Neurons are exposed to oxidative stress due to high oxygen consumption during metabolic activity in the brain. Accordingly, DNA damage can occur and accumulate, resulting in genome instability. In this context, imbalances in brain trace element homeostasis are a matter of concern, especially regarding iron, copper, manganese, zinc, and selenium. Although trace elements are essential for brain physiology, excess and deficient conditions are considered to impair neuronal maintenance. Besides increasing oxidative stress, DNA damage response and repair of oxidative DNA damage are affected by trace elements. Hence, a balanced trace element homeostasis is of particular importance to safeguard neuronal genome integrity and prevent neuronal loss. This review summarises the current state of knowledge on the impact of deficient, as well as excessive iron, copper, manganese, zinc, and selenium levels on neuronal genome stability.

Keywords: Base excision repair; Brain; DNA damage (response); Genome stability; Trace element homeostasis; Trace elements.

Graphical abstract

Fig. 1

Simplified scheme illustrating mammalian short- and long-patch BER. The figure highlights the key BER enzymes and their interactions with the TEs Fe, Cu, Mn, Zn, and Se in neuronal cells summarized in this review. In this context, by TE dyshomeostasis affected enzymes are illustrated in black, whereas other important enzymes are highlighted in grey. APE1 = apurinic/apyrimidinic endonuclease 1; APTX = aprataxin; FEN1 = flap structure-specific endonuclease 1; LIG1/3 = ligase 1/3; MUTYH = mutY DNA glycosylase; NEIL1/2 = nei like DNA glycosylase 1/2; OGG1 = 8-oxoguanine DNA glycosylase; PARP1 = poly(ADP-ribose)polymerase 1; PARylation = poly(ADP-ribosyl)ation; PCNA = proliferating cell nuclear antigen; PNKP = polynucleotide kinase 3′-phosphatase; POLβ = DNA polymerase beta; POLδ/ε = polymerase δ/ε; TPD1 = tyrosyl-DNA phosphodiesterase 1; XRCC1 = X-ray repair cross complementing 1.

Fig. 2

Schematic overview of brain regions and distribution of Fe, Cu, Mn, Zn, and Se highlighting areas of TE enrichments under physiological conditions. Illustrated is a schematic longitudinal section of the brain with its five main brain regions. Additionally shown are the respective subsections for each main brain region with their particular TE enrichment. A detailed summary of the different TE brain concentrations is reviewed in Grochowski et al. [31,105].

Fig. 3

Simplified scheme illustrating interdependence between oxidative stress, DDR, and BER in the context of TE dyshomeostasis.