Tumor-associated APE1 variant exhibits reduced complementation efficiency but does not promote cancer cell phenotypes

Jennifer L. Illuzzi, Daniel R. McNeill, Paul Bastian, Boris Brenerman, Robert Wersto, Helen R. Russell, Fred Bunz, Peter J. McKinnon, Kevin G. Becker, David M. Wilson

Research output: Contribution to journalArticle

Abstract

Base excision repair (BER) is the major pathway for coping with most forms of endogenous DNA damage, and defects in the process have been associated with carcinogenesis. Apurinic/apyrimidinic endonuclease 1 (APE1) is a central participant in BER, functioning as a critical endonuclease in the processing of noncoding abasic sites in DNA. Evidence has suggested that APE1 missense mutants, as well as altered expression or localization of the protein, can contribute to disease manifestation. We report herein that the tumor-associated APE1 variant, R237C, shows reduced complementation efficiency of the methyl methanesulfonate hypersensitivity and impaired cell growth exhibited by APE1-deficient mouse embryonic fibroblasts. Overexpression of wild-type APE1 or the R237C variant in the nontransformed C127I mouse cell line had no effect on proliferation, cell cycle status, steady-state DNA damage levels, mitochondrial function, or cellular transformation. A human cell line heterozygous for an APE1 knockout allele had lower levels of endogenous APE1, increased cellular sensitivity to DNA-damaging agents, impaired proliferation with time, and a distinct global gene expression pattern consistent with a stress phenotype. Our results indicate that: (i) the tumor-associated R237C variant is a possible susceptibility factor, but not likely a driver of cancer cell phenotypes, (ii) overexpression of APE1 does not readily promote cellular transformation, and (iii) haploinsufficiency at the APE1 locus can have profound cellular consequences, consistent with BER playing a critical role in proliferating cells. Environ. Mol. Mutagen. 58:84–98, 2017.

Original languageEnglish (US)
Pages (from-to)84-98
Number of pages15
JournalEnvironmental and Molecular Mutagenesis
Volume58
Issue number2
DOIs
StatePublished - Mar 1 2017

Fingerprint

Endonucleases
Phenotype
Neoplasms
DNA Repair
DNA Damage
DNA-(Apurinic or Apyrimidinic Site) Lyase
Methyl Methanesulfonate
Haploinsufficiency
Cell Line
DNA
Mutagens
Cell Cycle
Hypersensitivity
Carcinogenesis
Fibroblasts
Alleles
Gene Expression
Growth

Keywords

  • APE1/APEX1
  • base excision repair
  • cancer susceptibility
  • haploinsufficiency
  • transformation

ASJC Scopus subject areas

  • Epidemiology
  • Genetics(clinical)
  • Health, Toxicology and Mutagenesis

Cite this

Illuzzi, J. L., McNeill, D. R., Bastian, P., Brenerman, B., Wersto, R., Russell, H. R., ... Wilson, D. M. (2017). Tumor-associated APE1 variant exhibits reduced complementation efficiency but does not promote cancer cell phenotypes. Environmental and Molecular Mutagenesis, 58(2), 84-98. https://doi.org/10.1002/em.22074

Tumor-associated APE1 variant exhibits reduced complementation efficiency but does not promote cancer cell phenotypes. / Illuzzi, Jennifer L.; McNeill, Daniel R.; Bastian, Paul; Brenerman, Boris; Wersto, Robert; Russell, Helen R.; Bunz, Fred; McKinnon, Peter J.; Becker, Kevin G.; Wilson, David M.

In: Environmental and Molecular Mutagenesis, Vol. 58, No. 2, 01.03.2017, p. 84-98.

Research output: Contribution to journalArticle

Illuzzi, JL, McNeill, DR, Bastian, P, Brenerman, B, Wersto, R, Russell, HR, Bunz, F, McKinnon, PJ, Becker, KG & Wilson, DM 2017, 'Tumor-associated APE1 variant exhibits reduced complementation efficiency but does not promote cancer cell phenotypes', Environmental and Molecular Mutagenesis, vol. 58, no. 2, pp. 84-98. https://doi.org/10.1002/em.22074
Illuzzi, Jennifer L. ; McNeill, Daniel R. ; Bastian, Paul ; Brenerman, Boris ; Wersto, Robert ; Russell, Helen R. ; Bunz, Fred ; McKinnon, Peter J. ; Becker, Kevin G. ; Wilson, David M. / Tumor-associated APE1 variant exhibits reduced complementation efficiency but does not promote cancer cell phenotypes. In: Environmental and Molecular Mutagenesis. 2017 ; Vol. 58, No. 2. pp. 84-98.
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