Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

REV3L 3′UTR 460 T>C polymorphism in microRNA target sites contributes to lung cancer susceptibility

Oncogene volume 32, pages 242–250 (2013)Cite this article

Subjects

Abstract

REV3Lp, the catalytic subunit of DNA polymerase zeta, is the major participant in translesion DNA synthesis. Recent evidence suggests that REV3L has an important role in the maintenance of genome stability despite its mutagenic characteristics. Such a function makes it a cancer susceptibility candidate gene. To investigate association between REV3L polymorphisms and lung cancer risk in a Chinese population, we first genotyped 15 common polymorphisms of the REV3L gene and found that three single nucleotide polymorphisms (rs465646, rs459809 and rs1002481) were significantly associated with lung cancer risk. One of the strongest associations observed was for the 3′-terminal untranslated region (3′UTR) 460 T>C polymorphism (rs465646) (adjusted odds ratio (OR)=0.69 for TC/CC; P=0.007, compared with TT). Similar results were obtained in a subsequent replication study (adjusted OR=0.72; P=0.016). Combined data from the two studies of 1072 lung cancer patients and 1064 cancer-free controls generated an even stronger association (adjusted OR=0.71; P=3.04 × 10−4). This 3′UTR 460 T>C variant was predicted to modulate the binding of several micro RNAs. Surface plasmon resonance analysis and luciferase assays showed that the T allele demonstrated a stronger binding affinity for miR-25 and miR-32, resulting in significantly weaker reporter expression levels. Additional experiments revealed that miR-25/32 could downregulate endogenous REV3L. Furthermore, the tumor-suppressing role of REV3L was confirmed by the foci formation assay. These results support our hypothesis that the REV3L rs465646 variant modifies lung cancer susceptibility in Chinese Han population by affecting miRNA-mediated gene regulation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D . Global cancer statistics. CA Cancer J Clin 2011; 61: 69–90.

    Article  Google Scholar 

  2. Hoeijmakers JH . Genome maintenance mechanisms are critical for preventing cancer as well as other aging-associated diseases. Mech Ageing Dev 2007; 128: 460–462.

    Article  CAS  Google Scholar 

  3. Sonoda E, Okada T, Zhao GY, Tateishi S, Araki K, Yamaizumi M et al. Multiple roles of Rev3, the catalytic subunit of polzeta in maintaining genome stability in vertebrates. Embo J 2003; 22: 3188–3197.

    Article  CAS  Google Scholar 

  4. Friedberg EC, Lehmann AR, Fuchs RP . Trading places: how do DNA polymerases switch during translesion DNA synthesis? Mol Cell 2005; 18: 499–505.

    Article  CAS  Google Scholar 

  5. Venkatesan RN, Bielas JH, Loeb LA . Generation of mutator mutants during carcinogenesis. DNA Repai (Amst) 2006; 5: 294–302.

    Article  CAS  Google Scholar 

  6. Matsuda T, Bebenek K, Masutani C, Hanaoka F, Kunkel TA . Low fidelity DNA synthesis by human DNA polymerase-eta. Nature 2000; 404: 1011–1013.

    Article  CAS  Google Scholar 

  7. Johnson RE, Washington MT, Haracska L, Prakash S, Prakash L . Eukaryotic polymerases iota and zeta act sequentially to bypass DNA lesions. Nature 2000; 406: 1015–1019.

    Article  CAS  Google Scholar 

  8. Zhang Y, Yuan F, Wu X, Wang Z . Preferential incorporation of G opposite template T by the low-fidelity human DNA polymerase iota. Mol Cell Biol 2000; 20: 7099–7108.

    Article  CAS  Google Scholar 

  9. Gan GN, Wittschieben JP, Wittschieben BØ, Wood RD . DNA polymerase zeta (pol zeta) in higher eukaryotes. Cell Res 2008; 18: 174–183.

    Article  CAS  Google Scholar 

  10. Lawrence CW, Maher VM . Mutagenesis in eukaryotes dependent on DNA polymerase zeta and Rev1p. Philos Trans R Soc Lond B Biol Sci 2001; 356: 41–46.

    Article  CAS  Google Scholar 

  11. Lemontt JF . Induction of forward mutations in mutationally defective yeast. Mol Gen Genet 1972; 119: 27–42.

    Article  CAS  Google Scholar 

  12. Wittschieben JP, Reshmi SC, Gollin SM, Wood RD . Loss of DNA polymerase zeta causes chromosomal instability in mammalian cells. Cancer Res 2006; 66: 134–142.

    Article  CAS  Google Scholar 

  13. Nojima K, Hochegger H, Saberi A, Fukushima T, Kikuchi K, Yoshimura M et al. Multiple repair pathways mediate tolerance to chemotherapeutic cross-linking agents in vertebrate cells. Cancer Res 2005; 65: 11704–11711.

    Article  CAS  Google Scholar 

  14. Bemark M, Khamlichi AA, Davies SL, Neuberger MS . Disruption of mouse polymerase zeta (Rev3) leads to embryonic lethality and impairs blastocyst development in vitro. Curr Biol 2000; 10: 1213–1216.

    Article  CAS  Google Scholar 

  15. Esposito G, Godindagger I, Klein U, Yaspo ML, Cumano A, Rajewsky K . Disruption of the Rev3l-encoded catalytic subunit of polymerase zeta in mice results in early embryonic lethality. Curr Biol 2000; 10: 1221–1224.

    Article  CAS  Google Scholar 

  16. Zhu F, Jin CX, Song T, Yang J, Guo L, Yu YN . Response of human REV3 gene to gastric cancer inducing carcinogen N-methyl-N′-nitro-N-nitrosoguanidine and its role in mutagenesis. World J Gastroenterol 2003; 9: 888–893.

    Article  CAS  Google Scholar 

  17. Brondello JM, Pillaire MJ, Rodriguez C, Gourraud PA, Selves J, Cazaux C et al. Novel evidences for a tumor suppressor role of Rev3, the catalytic subunit of Pol zeta. Oncogene 2008; 27: 6093–6101.

    Article  CAS  Google Scholar 

  18. Pan Q, Fang Y, Xu Y, Zhang K, Hu X . Down-regulation of DNA polymerases kappa, eta, iota, and zeta in human lung, stomach, and colorectal cancers. Cancer Lett 2005; 217: 139–147.

    Article  CAS  Google Scholar 

  19. Hu Z, Wang H, Shao M, Jin G, Sun W, Wang Y et al. Genetic variants in MGMT and risk of lung cancer in Southeastern Chinese: a haplotype-based analysis. Hum Mutat 2007; 28: 431–440.

    Article  CAS  Google Scholar 

  20. Lu J, Zhang S, Chen D, Wang H, Wu W, Wang X et al. Functional characterization of a promoter polymorphism in APE1/Ref-1 that contributes to reduced lung cancer susceptibility. FASEB J 2009; 23: 3459–3469.

    Article  CAS  Google Scholar 

  21. Wang QZ, Xu W, Habib N, Xu R . Potential uses of microRNA in lung cancer diagnosis, prognosis, and therapy. Curr Cancer Drug Targets 2009; 9: 572–594.

    Article  CAS  Google Scholar 

  22. Wang HB, Zhang SY, Wang S, Lv J, Wu WT, Weng L et al. REV3L confers chemoresistance to cisplatin in human gliomas: The potential of its RNAi for synergistic therapy. Neuro Oncol 2009; 11: 790–802.

    Article  Google Scholar 

  23. Lehmann AR . Replication of damaged DNA by translesion synthesis in human cells. FEBS Lett 2005; 579: 873–876.

    Article  CAS  Google Scholar 

  24. Rockwell S, Yuan J, Peretz S, Glazer PM . Genomic instability in cancer. Novartis Found Symp 2001; 240: 133–142; discussion 142-151.

    CAS  PubMed  Google Scholar 

  25. Gibbs PE, McGregor WG, Maher VM, Nisson P, Lawrence CW . A human homolog of the Saccharomyces cerevisiae REV3 gene, which encodes the catalytic subunit of DNA polymerase zeta. Proc Natl Acad Sci USA 1998; 95: 6876–6880.

    Article  CAS  Google Scholar 

  26. Lin W, Wu X, Wang Z . A full-length cDNA of hREV3 is predicted to encode DNA polymerase zeta for damage-induced mutagenesis in humans. Mutat Res 1999; 433: 89–98.

    Article  CAS  Google Scholar 

  27. Datta A, Jinks-Robertson S . Association of increased spontaneous mutation rates with high levels of transcription in yeast. Science 1995; 268: 1616–1619.

    Article  CAS  Google Scholar 

  28. Kajiwara K, Nagawawa H, Shimizu-Nishikawa S, Ookuri T, Kimura M, Sugaya E . Molecular characterization of seizure-related genes isolated by differential screening. Biochem Biophys Res Commun 1996; 219: 795–799.

    Article  CAS  Google Scholar 

  29. Krieg AJ, Hammond EM, Giaccia AJ . Functional analysis of p53 binding under differential stresses. Mol Cell Biol 2006; 26: 7030–7045.

    Article  CAS  Google Scholar 

  30. Kim VN, Nam JW . Genomics of microRNA. Trends Genet 2006; 22: 165–173.

    Article  CAS  Google Scholar 

  31. Doench JG, Sharp PA . Specificity of microRNA target selection in translational repression. Genes Dev 2004; 18: 504–511.

    Article  CAS  Google Scholar 

  32. Vatolin S, Navaratne K, Weil RJ . A novel method to detect functional microRNA targets. J Mol Biol 2006; 358: 983–996.

    Article  CAS  Google Scholar 

  33. Saunders MA, Liang H, Li WH . Human polymorphism at microRNAs and microRNA target sites. Proc Natl Acad Sci USA 2007; 104: 3300–3305.

    Article  CAS  Google Scholar 

  34. Yu Z, Li Z, Jolicoeur N, Zhang L, Fortin Y, Wang E et al. Aberrant allele frequencies of the SNPs located in microRNA target sites are potentially associated with human cancers. Nucleic Acids Res 2007; 35: 4535–4541.

    Article  CAS  Google Scholar 

  35. Nicoloso MS, Sun H, Spizzo R, Kim H, Wickramasinghe P, Shimizu M et al. Single-nucleotide polymorphisms inside microRNA target sites influence tumor susceptibility. Cancer Res 2010; 70: 2789–2798.

    Article  CAS  Google Scholar 

  36. Clop A, Marcq F, Takeda H, Pirottin D, Tordoir X, Bibe B et al. A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep. Nat Genet 2006; 38: 813–818.

    Article  CAS  Google Scholar 

  37. Mishra PJ, Humeniuk R, Mishra PJ, Longo-Sorbello GS, Banerjee D, Bertino JR . A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance. Proc Natl Acad Sci USA 2007; 104: 13513–13518.

    Article  CAS  Google Scholar 

  38. Wang G, van der Walt JM, Mayhew G, Li YJ, Zuchner S, Scott WK et al. Variation in the miRNA-433 binding site of FGF20 confers risk for Parkinson disease by overexpression of alpha-synuclein. Am J Hum Genet 2008; 82: 283–289.

    Article  CAS  Google Scholar 

  39. Chen D, Jin G, Wang Y, Wang H, Liu H, Liu Y et al. Genetic variants in peroxisome proliferator-activated receptor-gamma gene are associated with risk of lung cancer in a Chinese population. Carcinogenesis 2008; 29: 342–350.

    Article  Google Scholar 

Download references

Acknowledgements

This work was partially supported by the Shanghai Science and Technology Research Program (Grants 09JC1402200 and 10410709100), the Natural Science Foundation of China (Grants 30800622, 81001114 and 81020108028), the Scientific Research Foundation for the Returned Overseas Chinese Scholars (State Education Ministry), the Doctoral Fund of the Ministry of Education of China and the Shanghai Key Subject Project for Public Health (Grant 08GWZX0301).

Author information

Author notes

  1. S Zhang and H Chen: These authors contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China

    S Zhang, H Chen, X Zhao, J Lu, W Wu & D Lu

  2. School of Radiation Medicine and P,

    S Zhang, J Cao & J Tong

  3. rotection,

    S Zhang, J Cao & J Tong

  4. , Medical College of Soochow University, Suzhou, China

    S Zhang, J Cao & J Tong

  5. Department of Epidemiology and Biostatistics, Cancer Center of Nanjing Medical University, Nanjing, China

    H Shen

  6. Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Q Wei

Authors
  1. S Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. X Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Tong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. W Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. H Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Q Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. D Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D Lu.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, S., Chen, H., Zhao, X. et al. REV3L 3′UTR 460 T>C polymorphism in microRNA target sites contributes to lung cancer susceptibility. Oncogene 32, 242–250 (2013). https://doi.org/10.1038/onc.2012.32

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2012.32

Keywords

This article is cited by

Search

Advanced search

Quick links