Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2011;24 Suppl 2(0 2):183-98.
doi: 10.3233/JAD-2011-110281.

Oxidative genome damage and its repair in neurodegenerative diseases: function of transition metals as a double-edged sword

Muralidhar L Hegde  1 , Pavana M Hegde, K S Rao, Sankar Mitra
Affiliations
Review

Oxidative genome damage and its repair in neurodegenerative diseases: function of transition metals as a double-edged sword

Muralidhar L Hegde et al. J Alzheimers Dis. 2011.

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 damage is predominantly repaired via the highly conserved and regulated base excision/SSB repair (BER/SSBR) pathway. We recently made an interesting discovery that the transition metals iron and copper, 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 the therapeutic potential of metal chelators in restoring DNA repair capacity.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1. A schematic illustration of repair of ROS-induced DNA damage via BER/SSBR pathways
ROS can induce oxidized bases (represented as a *), oxidized AP sites and SSBs with blocked termini. In addition, normal AP sites may be generated (by ROS) indirectly via deamination of C to form U which is removed by monofunctional UDG. After the base excision/AP lyase step in BER, the two pathways converge to common steps of cleaning blocked termini (in red), followed by gap-filling repair synthesis (in blue) and nick sealing. Divergent repair synthesis reactions with patch size of 1-nt (SN-BER) vs. 2–8 nts (LP-BER) are shown. Other details are given in the text.
Fig. 2
Fig. 2. Metal genotoxicity in neurodegenerative diseases: A case of double jeopardy
Iron and copper accumulating in human brain with neurodegenerative diseases induce oxidative genome damage via free radical generation and act as a ‘double-edged sword’ by also inhibiting damage repair by binding to the repair enzymes. Specific chelators and a reducing agent or curcumin allows repair to occur.
Fig. 3
Fig. 3. Structure of curcumin (A), chemistry of metal chelation (B) and antioxidant properties (C)
Curcumin exhibits keto-enol tautomerism in aqueous solution. Complexes of curcumin with iron (1:3) and copper (2:1 or 1:1, not shown) suggest its strong chelating activity. Curcumin also acts as a reducing agent as illustrated in (C).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Dawson TL, Gores GJ, Nieminen AL, Herman B, Lemasters JJ. Mitochondria as a source of reactive oxygen species during reductive stress in rat hepatocytes. Am J Physiol. 1993;264:C961–C967. - PubMed
    1. Lindahl T. Instability and decay of the primary structure of DNA. Nature. 1993;362:709–715. - PubMed
    1. Mitra S, Izumi T, Boldogh I, Bhakat KK, Hill JW, Hazra TK. Choreography of oxidative damage repair in mammalian genomes. Free Radic Biol Med. 2002;33:15–28. - PubMed
    1. Hanawalt PC. Emerging links between premature ageing and defective DNA repair. Mech Ageing Dev. 2008;129:503–505. - PMC - PubMed
    1. Dorszewska J, Florczak J, Rozycka A, Kempisty B, Jaroszewska-Kolecka J, Chojnacka K, Trzeciak WH, Kozubski W. Oxidative DNA damage and level of thiols as related to polymorphisms of MTHFR, MTR, MTHFD1 in Alzheimer's and Parkinson's diseases. Acta Neurobiol Exp (Wars) 2007;67:113–129. - PubMed

Publication types

MeSH terms