Interaction of the human DNA glycosylase NEIL1 with proliferating cell nuclear antigen. The potential for replication-associated repair of oxidized bases in mammalian genomes - PubMed (original) (raw)
. 2008 Feb 8;283(6):3130-3140.
doi: 10.1074/jbc.M709186200. Epub 2007 Nov 21.
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- PMID: 18032376
- DOI: 10.1074/jbc.M709186200
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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 Dou et al. J Biol Chem. 2008.
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Abstract
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 delta 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.
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- P01 AI062885/AI/NIAID NIH HHS/United States
- P01 AG021830/AG/NIA NIH HHS/United States
- P30 ES006676-129007/ES/NIEHS NIH HHS/United States
- R01 CA063154/CA/NCI NIH HHS/United States
- P01 AG021830-040003/AG/NIA NIH HHS/United States
- P01 CA092584/CA/NCI NIH HHS/United States
- P30 ES06676/ES/NIEHS NIH HHS/United States
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- R01 CA081063/CA/NCI NIH HHS/United States
- R01 CA102271/CA/NCI NIH HHS/United States
- T32-07254/PHS HHS/United States
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