Increased risk of lung cancer associated with a functionally impaired polymorphic variant of the human DNA glycosylase NEIL2

Sanjib Dey, Amit K. Maiti, Muralidhar L. Hegde, Pavana M. Hegde, Istvan Boldogh, Partha S. Sarkar, Sherif Z. Abdel-Rahman, Altaf H. Sarker, Bo Hang, Jingwu Xie, Alan E. Tomkinson, Mian Zhou, Binghui Shen, Guanghai Wang, Chen Wu, Dianke Yu, Dongxin Lin, Victor Cardenas, Tapas K. Hazra

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Human NEIL2, one of five oxidized base-specific DNA glycosylases, is unique in preferentially repairing oxidative damage in transcribed genes. Here we show that depletion of NEIL2 causes a 6-7-fold increase in spontaneous mutation frequency in the HPRT gene of the V79 Chinese hamster lung cell line. This prompted us to screen for NEIL2 variants in lung cancer patients' genomic DNA. We identified several polymorphic variants, among which R103Q and R257L were frequently observed in lung cancer patients. We then characterized these variants biochemically, and observed a modest decrease in DNA glycosylase activity relative to the wild type (WT) only with the R257L mutant protein. However, in reconstituted repair assays containing WT NEIL2 or its R257L and R103Q variants together with other DNA base excision repair (BER) proteins (PNKP, Polβ, Lig IIIα and XRCC1) or using NEIL2-FLAG immunocomplexes, an ∼5-fold decrease in repair was observed with the R257L variant compared to WT or R103Q NEIL2, apparently due to the R257L mutant's lower affinity for other repair proteins, particularly Polβ. Notably, increased endogenous DNA damage was observed in NEIL2 variant (R257L)-expressing cells relative to WT cells. Taken together, our results suggest that the decreased DNA repair capacity of the R257L variant can induce mutations that lead to lung cancer development.

Original languageEnglish (US)
Pages (from-to)570-578
Number of pages9
JournalDNA Repair
Volume11
Issue number6
DOIs
StatePublished - Jun 1 2012

Keywords

  • BER
  • Lung cancer
  • NEIL2
  • SNP

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Dey, S., Maiti, A. K., Hegde, M. L., Hegde, P. M., Boldogh, I., Sarkar, P. S., Abdel-Rahman, S. Z., Sarker, A. H., Hang, B., Xie, J., Tomkinson, A. E., Zhou, M., Shen, B., Wang, G., Wu, C., Yu, D., Lin, D., Cardenas, V., & Hazra, T. K. (2012). Increased risk of lung cancer associated with a functionally impaired polymorphic variant of the human DNA glycosylase NEIL2. DNA Repair, 11(6), 570-578. https://doi.org/10.1016/j.dnarep.2012.03.005