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Journal of Nucleic Acids
Volume 2010 (2010), Article ID 872180, 11 pages
Research Article

Elevated Levels of DNA Strand Breaks Induced by a Base Analog in the Human Cell Line with the P32T ITPA Variant

1Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA
2Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia
3Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198-6025, USA

Received 26 April 2010; Accepted 11 July 2010

Academic Editor: Ashis Basu

Copyright © 2010 Irina S.-R. Waisertreiger et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Base analogs are powerful antimetabolites and dangerous mutagens generated endogenously by oxidative stress, inflammation, and aberrant nucleotide biosynthesis. Human inosine triphosphate pyrophosphatase (ITPA) hydrolyzes triphosphates of noncanonical purine bases (i.e., ITP, dITP, XTP, dXTP, or their mimic: 6-hydroxyaminopurine (HAP) deoxynucleoside triphosphate) and thus regulates nucleotide pools and protects cells from DNA damage. We demonstrate that the model purine base analog HAP induces DNA breaks in human cells and leads to elevation of levels of ITPA. A human polymorphic allele of the ITPA, 94C- A encodes for the enzyme with a P32T amino-acid change and leads to accumulation of nonhydrolyzed ITP. The polymorphism has been associated with adverse reaction to purine base-analog drugs. The level of both spontaneous and HAP-induced DNA breaks is elevated in the cell line with the ITPA P32T variant. The results suggested that human ITPA plays a pivotal role in the protection of DNA from noncanonical purine base analogs.