The hSNM1B/Apollo variant rs11552449 is associated with cellular sensitivity towards mitomycin C and ionizing radiation

DNA Repair (Amst). 2018 Dec;72:93-98. doi: 10.1016/j.dnarep.2018.09.004. Epub 2018 Sep 12.

Abstract

The polymorphism rs11552449 (c.181C > T, p.His61Tyr) in the hSNM1B/Apollo gene has been repeatedly shown to be associated with an increased risk for breast cancer. The aim of the current study was to investigate the association between rs11552449 and the degree of cellular sensitivity to mitomycin C (MMC) and ionizing radiation (IR). A total of 69 lymphoblastoid cell lines (LCLs) from generally healthy donors were tested for their sensitivity towards MMC and IR in growth inhibition experiments. LCLs heterozygous for rs11552449 were significantly more sensitive to MMC and IR than homozygous cells with the CC genotype (p < 0.05 and p < 0.01 for MMC and IR, respectively) and in the case of MMC also for the TT genotype (p < 0.01). Interestingly, heterozygous CT cells expressed significantly more full length hSNM1B/Apollo mRNA than cells with the homozygous CC (p < 0.0001) or TT genotypes (p < 0.00001). Thus, the observed higher sensitivity of cell lines heterozygous for rs11552449 towards MMC and IR may be a consequence of differential expression of hSNM1B/Apollo associated with rs11552449, a feature which has not been ascribed to this polymorphism before. Interestingly, relative leukocyte telomere length (rLTL) analyzed in a subset of these cells (N = 62) and in leukocytes of N = 1710 Berlin Aging Study II (BASE-II) participants was not associated with rs11552449. The results suggest that hSNM1B/Apollo is causal for the repeatedly reported association between rs11552449 and breast cancer. These results pave the way for further research regarding the clinical impact of rs11552449, e.g. on the clinical outcome of cancer therapy with DNA interstrand crosslinking agents and IR.

Keywords: Apollo; BASE-II; Berlin Aging Study II; Breast cancer; DCLRE1B; Ionizing radiation; LCLs; Lymphoblastoid cell lines; Mitomycin C; Telomere length; hSNM1B; rs11552449.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • DNA Repair Enzymes / genetics*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / radiation effects
  • Genotype
  • Humans
  • Mitomycin / pharmacology*
  • Nuclear Proteins / genetics*
  • Polymorphism, Single Nucleotide*
  • Radiation Tolerance / genetics*

Substances

  • Nuclear Proteins
  • Mitomycin
  • DCLRE1B protein, human
  • DNA Repair Enzymes