Oxidative Genome Damage and its Repair in Neurodegenerative Diseases: Function of Transition Metals as a Double-Edged Sword

Abstract

The neurons in the central nervous system (CNS) with high O2 consumption and prolonged life span are chronically exposed to high levels of reactive oxygen species (ROS). Accumulation of ROS-induced genome damage in the form of oxidized bases and single-strand breaks (SSBs) as well as their defective or reduced repair in the brain has been implicated in the etiology of various neurological disorders including Alzheimer’s/Parkinson’s diseases (AD/PD). Although inactivating mutations in some DNA repair genes have been linked to hereditary neurodegenerative diseases, the underlying mechanisms of repair deficiencies for the sporadic diseases is not understood. The ROS-induced DNA damages are predominantly repaired via highly conserved and regulated base excision/SSB repair (BER/SSBR) pathway. We recently made an interesting discovery that transition metals iron (Fe) and copper (Cu) which accumulate excessively in the brains of AD, PD and other neurodegenerative diseases, act as a ‘double-edged sword’ by inducing genotoxic ROS and inhibiting DNA damage repair at the same time. These metals inhibit the base excision activity of NEIL family DNA glycosylases by oxidizing them, changing their structure, and inhibiting their binding to downstream repair proteins. Metal chelators and reducing agents partially reverse the inhibition, while curcumin with both chelating and reducing activities reverses the inhibition nearly completely. In this review, we have discussed the possible etiological linkage of BER/SSBR defects to neurodegenerative diseases and therapeutic potential of metal chelators in restoring DNA repair capacity.

Noninvasive mapping of the redox status in septic mouse by in vivo electron paramagnetic resonance imaging

“…Numerous results have shown that oxidative stress plays a significant role in the pathogenesis of many neurodegenerative diseases in the brain. Therefore, noninvasive visualization of the redox status in the brain may be important for elucidating the involvement of ROS in many diseases such as brain tumors, stroke and Alzheimer's disease [9][10][11]. EPR imaging and magnetic resonance imaging (MRI) have frequently been used in noninvasive imaging studies of ROS in vivo [12][13][14][15][16][17][18].…”

Innate Inflammation Induced by the 8-Oxoguanine DNA Glycosylase-1–KRAS–NF-κB Pathway

“…Moreover, the accumulation of 8-oxoG along with other oxidatively modified bases in the mammalian genome has been associated with a loss of cellular/tissue homeostasis, and is believed to contribute to various inflammatory processes and aging-related diseases (5, 6). In mammalian cells, oxidatively modified base lesions are repaired by the base-specific DNA glycosylases OGG1, endonuclease III-like protein 1 (NTH1), and Nei -like (NEIL1, NEIL2 and NEIL3) (7, 8). OGG1 and NTH1 incise the DNA strand via β-lyase activity, thereby generating 3′-phospho-α,β-unsaturated aldehyde terminus (3′dRP) and 5′-phosphate, while NEIL1,2 and 3 have βδ-lyase activity, thus generating 3′- and 5′ phosphate (3′P and 5′P) at the strand gaps.…”

Base Excision Repair Facilitates a Functional Relationship Between Guanine Oxidation and Histone Demethylation

“…Such damage can arise from numerous exogenous and endogenous sources, resulting in a multitude of detrimental cellular effects, including mutations, genome rearrangements, altered gene expression, and the onset of cell death or senescence (9,49,50). As depicted in Figure 1 and extensively reviewed elsewhere (88), many proteins are involved in the BER pathway to remove the base lesions and complete repair.…”