Specific Inhibition of NEIL-initiated repair of oxidized base damage in human genome by copper and iron: potential etiological linkage to neurodegenerative diseases.

The Journal of Biological Chemistry
Muralidhar L HegdeSankar Mitra

Abstract

Dyshomeostasis of transition metals iron and copper as well as accumulation of oxidative DNA damage have been implicated in multitude of human neurodegenerative diseases, including Alzheimer disease and Parkinson disease. These metals oxidize DNA bases by generating reactive oxygen species. Most oxidized bases in mammalian genomes are repaired via the base excision repair pathway, initiated with one of four major DNA glycosylases: NTH1 or OGG1 (of the Nth family) or NEIL1 or NEIL2 (of the Nei family). Here we show that Fe(II/III) and Cu(II) at physiological levels bind to NEIL1 and NEIL2 to alter their secondary structure and strongly inhibit repair of mutagenic 5-hydroxyuracil, a common cytosine oxidation product, both in vitro and in neuroblastoma (SH-SY5Y) cell extract by affecting the base excision and AP lyase activities of NEILs. The specificity of iron/copper inhibition of NEILs is indicated by a lack of similar inhibition of OGG1, which also indicated that the inhibition is due to metal binding to the enzymes and not DNA. Fluorescence and surface plasmon resonance studies show submicromolar binding of copper/iron to NEILs but not OGG1. Furthermore, Fe(II) inhibits the interaction of NEIL1 with downstream base excision r...Continue Reading

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Citations

Jul 31, 2013·Proceedings of the National Academy of Sciences of the United States of America·Muralidhar L HegdeSankar Mitra
Dec 12, 2012·Antioxidants & Redox Signaling·Renato X SantosGeorge Perry
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Jul 10, 2020·Journal of Neuroscience Research·Ali ShahandehChristine T O Nguyen
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Feb 17, 2019·Proceedings of the National Academy of Sciences of the United States of America·Joy MitraMuralidhar L Hegde
Feb 20, 2021·Redox Biology·Viktoria K WandtTanja Schwerdtle

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