Oncotarget

Research Papers:

S-nitrosation on zinc finger motif of PARP-1 as a mechanism of DNA repair inhibition by arsenite

Xixi Zhou _, Karen L. Cooper, Juliana Huestis, Huan Xu, Scott W. Burchiel, Laurie G. Hudson and Ke Jian Liu

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Oncotarget. 2016; 7:80482-80492. https://doi.org/10.18632/oncotarget.12613

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Abstract

Xixi Zhou1, Karen L. Cooper1, Juliana Huestis1, Huan Xu1, Scott W. Burchiel1, Laurie G. Hudson1, Ke Jian Liu1

1Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA

Correspondence to:

Xixi Zhou, email: xzhou@unm.edu

Keywords: arsenic, DNA repair, PARP-1, zinc finger, reactive nitrogen species

Received: August 04, 2016     Accepted: October 04, 2016     Published: October 12, 2016

ABSTRACT

Arsenic, a widely distributed carcinogen, is known to significantly amplify the impact of other carcinogens through inhibition of DNA repair. Our recent work suggests that reactive oxygen/nitrogen species (ROS/RNS) induced by arsenite (AsIII) play an important role in the inhibition of the DNA repair protein Poly(ADP-ribose) polymerase 1 (PARP-1). AsIII-induced ROS lead to oxidation of cysteine residues within the PARP-1 zinc finger DNA binding domain. However, the mechanism underlying RNS-mediated PARP inhibition by arsenic remains unknown. In this work, we demonstrate that AsIII treatment of normal human keratinocyte (HEKn) cells induced S-nitrosation on cysteine residues of PARP-1 protein, in a similar manner to a nitric oxide donor. S-nitrosation of PARP-1 could be reduced by 1400W (inducible nitric oxide synthase inhibitor) or c-PTIO (a nitric oxide scavenger). Furthermore, AsIII treatment of HEKn cells leads to zinc loss and inhibition of PARP-1 enzymatic activity. AsIII and 1400W/c-PTIO co-treatment demonstrate that these effects occur in an iNOS- and NO-dependent manner. Importantly, we confirmed S-nitrosation on the zinc finger DNA binding domain of PARP-1 protein. Taken together, AsIII induces S-nitrosation on PARP-1 zinc finger DNA binding domain by generating NO through iNOS activation, leading to zinc loss and inhibition of PARP-1 activity, thereby increasing retention of damaged DNA. These findings identify S-nitrosation as an important component of the molecular mechanism underlying AsIII inhibition of DNA repair, which may benefit the development of preventive and intervention strategies against AsIII co-carcinogenesis.


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