Characterization of rare NEIL1 variants found in East Asian populations

Irina Minko, Vladimir L. Vartanian, Naoto N. Tozaki, Oskar K. Linde, Pawel Jaruga, Sanem Hosbas Coskun, Erdem Coskun, Chunfeng Qu, Huan He, Chungui Xu, Taoyang Chen, Qianqian Song, Yuchen Jiao, Michael P. Stone, Martin Egli, Miral Dizdaroglu, Amanda McCullough, Robert (Stephen) Lloyd

Research output: Contribution to journalArticle

Abstract

The combination of chronic dietary exposure to the fungal toxin, aflatoxin B 1 (AFB 1 ), and hepatitis B viral (HBV)infection is associated with an increased risk for early onset hepatocellular carcinomas (HCCs). An in-depth knowledge of the mechanisms driving carcinogenesis is critical for the identification of genetic risk factors affecting the susceptibility of individuals who are HBV infected and AFB 1 exposed. AFB 1 -induced mutagenesis is characterized by G to T transversions. Hence, the DNA repair pathways that function on AFB 1 -induced DNA adducts or base damage from HBV-induced inflammation are anticipated to have a strong role in limiting carcinogenesis. These pathways define the mutagenic burden in the target tissues and ultimately limit cellular progression to cancer. Murine data have demonstrated that NEIL1 in the DNA base excision repair pathway was significantly more important than nucleotide excision repair relative to elevated risk for induction of HCCs. These data suggest that deficiencies in NEIL1 could contribute to the initiation of HCCs in humans. To investigate this hypothesis, publicly-available data on variant alleles of NEIL1 were analyzed and compared with genome sequencing data from HCC tissues derived from individuals residing in Qidong County (China). Three variant alleles were identified and the corresponding A51V, P68H, and G245R enzymes were characterized for glycosylase activity on genomic DNA containing a spectrum of oxidatively-induced base damage and an oligodeoxynucleotide containing a site-specific AFB 1 -formamidopyrimidine guanine adduct. Although the efficiency of the P68H variant was modestly decreased, the A51V and G245R variants showed nearly wild-type activities. Consistent with biochemical findings, molecular modeling of these variants demonstrated only slight local structural alterations. However, A51V was highly temperature sensitive suggesting that its biological activity would be greatly reduced. Overall, these studies have direct human health relevance pertaining to genetic risk factors and biochemical pathways previously not recognized as germane to induction of HCCs.

Original languageEnglish (US)
Pages (from-to)32-39
Number of pages8
JournalDNA Repair
Volume79
DOIs
StatePublished - Jul 1 2019

Fingerprint

Aflatoxin B1
Hepatocellular Carcinoma
Hepatitis B
DNA Repair
Repair
Population
DNA
Carcinogenesis
Alleles
Tissue
Mutagenesis
Molecular modeling
DNA Adducts
Mycotoxins
Oligodeoxyribonucleotides
Guanine
Virus Diseases
Bioactivity
China
Nucleotides

Keywords

  • Aflatoxin
  • Base excision repair
  • Formamidopyrimidines
  • Hepatocellular carcinoma
  • Thymine glycol

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Minko, I., Vartanian, V. L., Tozaki, N. N., Linde, O. K., Jaruga, P., Coskun, S. H., ... Lloyd, R. S. (2019). Characterization of rare NEIL1 variants found in East Asian populations. DNA Repair, 79, 32-39. https://doi.org/10.1016/j.dnarep.2019.05.001

Characterization of rare NEIL1 variants found in East Asian populations. / Minko, Irina; Vartanian, Vladimir L.; Tozaki, Naoto N.; Linde, Oskar K.; Jaruga, Pawel; Coskun, Sanem Hosbas; Coskun, Erdem; Qu, Chunfeng; He, Huan; Xu, Chungui; Chen, Taoyang; Song, Qianqian; Jiao, Yuchen; Stone, Michael P.; Egli, Martin; Dizdaroglu, Miral; McCullough, Amanda; Lloyd, Robert (Stephen).

In: DNA Repair, Vol. 79, 01.07.2019, p. 32-39.

Research output: Contribution to journalArticle

Minko, I, Vartanian, VL, Tozaki, NN, Linde, OK, Jaruga, P, Coskun, SH, Coskun, E, Qu, C, He, H, Xu, C, Chen, T, Song, Q, Jiao, Y, Stone, MP, Egli, M, Dizdaroglu, M, McCullough, A & Lloyd, RS 2019, 'Characterization of rare NEIL1 variants found in East Asian populations', DNA Repair, vol. 79, pp. 32-39. https://doi.org/10.1016/j.dnarep.2019.05.001
Minko I, Vartanian VL, Tozaki NN, Linde OK, Jaruga P, Coskun SH et al. Characterization of rare NEIL1 variants found in East Asian populations. DNA Repair. 2019 Jul 1;79:32-39. https://doi.org/10.1016/j.dnarep.2019.05.001
Minko, Irina ; Vartanian, Vladimir L. ; Tozaki, Naoto N. ; Linde, Oskar K. ; Jaruga, Pawel ; Coskun, Sanem Hosbas ; Coskun, Erdem ; Qu, Chunfeng ; He, Huan ; Xu, Chungui ; Chen, Taoyang ; Song, Qianqian ; Jiao, Yuchen ; Stone, Michael P. ; Egli, Martin ; Dizdaroglu, Miral ; McCullough, Amanda ; Lloyd, Robert (Stephen). / Characterization of rare NEIL1 variants found in East Asian populations. In: DNA Repair. 2019 ; Vol. 79. pp. 32-39.
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