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J. Biol. Chem., Vol. 283, Issue 6, 3130-3140, February 8, 2008

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Interaction of the Human DNA Glycosylase NEIL1 with Proliferating Cell Nuclear Antigen

THE POTENTIAL FOR REPLICATION-ASSOCIATED REPAIR OF OXIDIZED BASES IN MAMMALIAN GENOMES^*

Hong Dou¹², Corey A. Theriot¹³, Aditi Das, Muralidhar L. Hegde, Yoshihiro Matsumoto, Istvan Boldogh^¶, Tapas K. Hazra, Kishor K. Bhakat, and Sankar Mitra⁴

From the Departments of Biochemistry and Molecular Biology and ^¶Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555-1079 and the Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111

NEIL1 and NEIL2 compose a family of DNA glycosylases that is distinct from that of the other two DNA glycosylases, OGG1 and NTH1, all of which are involved in repair of oxidized bases in mammalian genomes. That the NEIL proteins, unlike OGG1 and NTH1, are able to excise base lesions from single-stranded DNA regions suggests their preferential involvement in repair during replication and/or transcription. Previous studies showing S phase-specific activation of NEIL1, but not NEIL2, suggested NEIL1 involvement in the repair of replicating DNA. Here, we show that human NEIL1 stably interacts both in vivo and in vitro with proliferating cell nuclear antigen (PCNA), the sliding clamp for DNA replication. PCNA stimulates NEIL1 activity in excising the oxidized base 5-hydroxyuracil from single-stranded DNA sequences including fork structures. PCNA enhances NEIL1 loading on the substrate. In contrast, although present in the NEIL2 immunocomplex, PCNA does not stimulate NEIL2. NEIL1 interacts with PCNA via a domain that is located in a region near the C terminus, dispensable for base excision activity. The interacting sequence in NEIL1, which lacks the canonical PCNA-binding motif, includes a sequence conserved in DNA polymerase and implicated in its PCNA binding. Mammalian two-hybrid analysis confirmed PCNA interaction with NEIL1. The G127A mutation in PCNA reduces its stimulatory activity, suggesting that the interdomain connector loop, a common binding interface of PCNA, is involved in NEIL1 binding. These results strongly support in vivo function of NEIL1 in preferential repair of oxidized bases in DNA prior to replication.

Received for publication, June 7, 2007 , and in revised form, November 8, 2007.

^* This work was supported in part by United States Public Health Service Grants R01 CA081063 and P30 ES06676 (to S. M.), R01 CA102271 (to T. K. H.), R01 CA063154 (to Y. M.), and P01 CA092584 (to S. M. and Y. M.). 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. 1 and 2.

¹ Both authors contributed equally to this work.

² Present address: Inst. of Molecular Medicine, University of Texas Health Science Center, Houston, TX 77030.

³ Supported by United States Public Health Service Predoctoral Training Grant T32-07254.

⁴ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, University of Texas Medical Branch, 6.136 Medical Research Bldg., Galveston, TX 77555-1079. Tel.: 409-772-1780/1788; Fax: 409-747-8608; E-mail: samitra{at}utmb.edu.

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