Interdependent genotoxic mechanisms of monomethylarsonous acid: Role of ROS-induced DNA damage and poly(ADP-ribose) polymerase-1 inhibition in the malignant transformation of urothelial cells

Shawn M. Wnek, Christopher L. Kuhlman, Jeannie M. Camarillo, Matthew K. Medeiros, Ke J. Liu, Serrine S. Lau, A. J. Gandolfi

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29 Scopus citations


Exposure of human bladder urothelial cells (UROtsa) to 50nM of the arsenic metabolite, monomethylarsonous acid (MMAIII), for 12weeks results in irreversible malignant transformation. The ability of continuous, low-level MMAIII exposure to cause an increase in genotoxic potential by inhibiting repair processes necessary to maintain genomic stability is unknown. Following genomic insult within cellular systems poly(ADP-ribose) polymerase-1 (PARP-1), a zinc finger protein, is rapidly activated and recruited to sites of DNA strand breaks. When UROtsa cells are continuously exposed to 50nM MMAIII, PARP-1 activity does not increase despite the increase in MMAIII-induced DNA single-strand breaks through 12weeks of exposure. When UROtsa cells are removed from continuous MMAIII exposure (2weeks), PARP-1 activity increases coinciding with a subsequent decrease in DNA damage levels. Paradoxically, PARP-1 mRNA expression and protein levels are elevated in the presence of continuous MMAIII indicating a possible mechanism to compensate for the inhibition of PARP-1 activity in the presence of MMAIII. The zinc finger domains of PARP-1 contain vicinal sulfhydryl groups which may act as a potential site for MMAIII to bind, displace zinc ion, and render PARP-1 inactive. Mass spectrometry analysis demonstrates the ability of MMAIII to bind a synthetic peptide representing the zinc-finger domain of PARP-1, and displace zinc from the peptide in a dose-dependent manner. In the presence of continuous MMAIII exposure, continuous 4-week zinc supplementation restored PARP-1 activity levels and reduced the genotoxicity associated with MMAIII. Zinc supplementation did not produce an overall increase in PARP-1 protein levels, decrease the levels of MMAIII-induced reactive oxygen species, or alter Cu-Zn superoxide dismutase levels. Overall, these results present two potential interdependent mechanisms in which MMAIII may increase the susceptibility of UROtsa cells to genotoxic insult and/or malignant transformation: elevated levels of MMAIII-induced DNA damage through the production of reactive oxygen species, and the direct MMAIII-induced inhibition of PARP-1.

Original languageEnglish (US)
Pages (from-to)1-13
Number of pages13
JournalToxicology and Applied Pharmacology
Issue number1
StatePublished - Nov 15 2011



  • Arsenic
  • Bladder cancer
  • Genotoxicity
  • Monomethylarsonous acid
  • Poly(ADP-ribose) polymerase-1
  • UROtsa

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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