Germ-line variant of human NTH1 DNA glycosylase induces genomic instability and cellular transformation

Heather A. Galick, Scott Kathe, Minmin Liu, Susan Robey-Bond, Dawit Kidane, Susan S. Wallace, Joann B. Sweasy

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Base excision repair (BER) removes at least 20,000 DNA lesions per human cell per day and is critical for the maintenance of genomic stability. We hypothesize that aberrant BER, resulting from mutations in BER genes, can lead to genomic instability and cancer. The first step in BER is catalyzed by DNA N-glycosylases. One of these, nth endonuclease III-like (NTH1), removes oxidized pyrimidines from DNA, including thymine glycol. The rs3087468 single nucleotide polymorphism of the NTH1 gene is a G-to-T base substitution that results in the NTH1 D239Y variant protein that occurs in ~6.2% of the global population and is found in Europeans, Asians, and sub-Saharan Africans. In this study, we functionally characterize the effect of the D239Y variant expressed in immortal but nontransformed human and mouse mammary epithelial cells. We demonstrate that expression of the D239Y variant in cells also expressing wild-type NTH1 leads to genomic instability and cellular transformation as assessed by anchorage-independent growth, focus formation, invasion, and chromosomal aberrations. We also show that cells expressing the D239Y variant are sensitive to ionizing radiation and hydrogen peroxide and accumulate double strand breaks after treatment with these agents. The DNA damage response is also activated in D239Y-expressing cells. In combination, our data suggest that individuals possessing the D239Y variant are at risk for genomic instability and cancer.

Original languageEnglish (US)
Pages (from-to)14314-14319
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number35
DOIs
StatePublished - Aug 27 2013
Externally publishedYes

Keywords

  • DNA repair
  • MCF10A breast epithelial cells
  • Mutagenesis

ASJC Scopus subject areas

  • General

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