The human Werner syndrome protein stimulates repair of oxidative DNA base damage by the DNA glycosylase NEIL1

Aditi Das, Istvan Boldogh, Wan Lee Jae, Jeanine A. Harrigan, Muralidhar L. Hegde, Jason Piotrowski, Nadja De Souza Pinto, William Ramos, Marc M. Greenberg, Tapas Hazra, Sankar Mitra, Vilhelm A. Bohr

Research output: Contribution to journalArticle

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Abstract

The mammalian DNA glycosylase, NEIL1, specific for repair of oxidatively damaged bases in the genome via the base excision repair pathway, is activated by reactive oxygen species and prevents toxicity due to radiation. We show here that the Werner syndrome protein (WRN), a member of the RecQ family of DNA helicases, associates with NEIL1 in the early damage-sensing step of base excision repair. WRN stimulates NEIL1 in excision of oxidative lesions from bubble DNA substrates. The binary interaction between NEIL1 and WRN (K D = 60 nM) involves C-terminal residues 288-349 of NEIL1 and the RecQ C-terminal (RQC) region of WRN, and is independent of the helicase activity WRN. Exposure to oxidative stress enhances the NEIL-WRN association concomitant with their strong nuclear co-localization. WRN-depleted cells accumulate some prototypical oxidized bases (e.g. 8-oxoguanine, FapyG, and FapyA) indicating a physiological function of WRN in oxidative damage repair in mammalian genomes. Interestingly, WRN deficiency does not have an additive effect on in vivo damage accumulation in NEIL1 knockdown cells suggesting that WRN participates in the same repair pathway as NEIL1.

Original languageEnglish
Pages (from-to)26591-26602
Number of pages12
JournalJournal of Biological Chemistry
Volume282
Issue number36
DOIs
StatePublished - Sep 7 2007

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Werner Syndrome
DNA Glycosylases
DNA Repair
DNA Damage
Repair
RecQ Helicases
Genome
DNA
Reactive Oxygen Species
Proteins
Oxidative Stress
Radiation
Genes
Oxidative stress
Toxicity
Association reactions
Substrates
8-hydroxyguanine

ASJC Scopus subject areas

  • Biochemistry

Cite this

The human Werner syndrome protein stimulates repair of oxidative DNA base damage by the DNA glycosylase NEIL1. / Das, Aditi; Boldogh, Istvan; Jae, Wan Lee; Harrigan, Jeanine A.; Hegde, Muralidhar L.; Piotrowski, Jason; Pinto, Nadja De Souza; Ramos, William; Greenberg, Marc M.; Hazra, Tapas; Mitra, Sankar; Bohr, Vilhelm A.

In: Journal of Biological Chemistry, Vol. 282, No. 36, 07.09.2007, p. 26591-26602.

Research output: Contribution to journalArticle

Das, A, Boldogh, I, Jae, WL, Harrigan, JA, Hegde, ML, Piotrowski, J, Pinto, NDS, Ramos, W, Greenberg, MM, Hazra, T, Mitra, S & Bohr, VA 2007, 'The human Werner syndrome protein stimulates repair of oxidative DNA base damage by the DNA glycosylase NEIL1', Journal of Biological Chemistry, vol. 282, no. 36, pp. 26591-26602. https://doi.org/10.1074/jbc.M703343200
Das, Aditi ; Boldogh, Istvan ; Jae, Wan Lee ; Harrigan, Jeanine A. ; Hegde, Muralidhar L. ; Piotrowski, Jason ; Pinto, Nadja De Souza ; Ramos, William ; Greenberg, Marc M. ; Hazra, Tapas ; Mitra, Sankar ; Bohr, Vilhelm A. / The human Werner syndrome protein stimulates repair of oxidative DNA base damage by the DNA glycosylase NEIL1. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 36. pp. 26591-26602.
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