HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 36, 26591-26602, September 7, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/36/26591    most recent M703343200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Das, A. Articles by Bohr, V. A. Search for Related Content PubMed PubMed Citation Articles by Das, A. Articles by Bohr, V. A. Social Bookmarking                      What's this?

The Human Werner Syndrome Protein Stimulates Repair of Oxidative DNA Base Damage by the DNA Glycosylase NEIL1^*

Aditi Das, Istvan Boldogh, Jae Wan Lee^¶, Jeanine A. Harrigan^¶, Muralidhar L. Hegde, Jason Piotrowski^¶, Nadja de Souza Pinto^¶, William Ramos^¶, Marc M. Greenberg^||, Tapas K. Hazra, Sankar Mitra, and Vilhelm A. Bohr^¶1

From the Department of Biochemistry and Molecular Biology and Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555, the ^¶Laboratory of Molecular Gerontology, NIA, National Institutes of Health, Baltimore, Maryland 21224, and the ^||Department of Chemistry, Johns Hopkins University, Baltimore, Maryland 21224

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.

Received for publication, April 20, 2007 , and in revised form, June 12, 2007.

^* This work was supported by NCI, National Institutes of Health (NIH) Grants 5 RO1 CA81063 (to S. M.), 1PO1 AG 021803 (to I. B. and S. M.), R01 CA102271 (to T. H.), RO1 CA-074954 (to M. M. G.), and PO1 CA 092584 (to S. M.); by NIEHS, NIH Center Grant ES06676; and by funds from the NIA, NIH intramural program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed: Laboratory of Molecular Gerontology, NIA, NIH, 5600 Nathan Shock Dr., Baltimore, MD 21224. Tel.: 410-558-8162; Fax: 410-558-8157; E-mail: vbohr{at}nih.gov.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				H. Dou, C. A. Theriot, A. Das, M. L. Hegde, Y. Matsumoto, I. Boldogh, T. K. Hazra, K. K. Bhakat, and S. Mitra Interaction of the Human DNA Glycosylase NEIL1 with Proliferating Cell Nuclear Antigen: THE POTENTIAL FOR REPLICATION-ASSOCIATED REPAIR OF OXIDIZED BASES IN MAMMALIAN GENOMES J. Biol. Chem., February 8, 2008; 283(6): 3130 - 3140. [Abstract] [Full Text] [PDF]

				R. M. Brosh Jr and V. A. Bohr Human premature aging, DNA repair and RecQ helicases Nucleic Acids Res., December 3, 2007; 35(22): 7527 - 7544. [Abstract] [Full Text] [PDF]