# Nickel and toxic topoisomerase I products

> **NIH NIH R01** · BROWN UNIVERSITY · 2024 · $358,875

## Abstract

Project Summary
Nickel (Ni) is a major industrial metal and a common environmental contaminant that is firmly
established as a human carcinogen. Inhalation of Ni compounds in occupationally exposed populations
has been found to cause lung and nasal cancers. Tumorigenicity of different forms of Ni was linked to
the intracellular presence of Ni(II) ions. Mechanisms of carcinogenic activity of Ni are poorly understood,
as Ni compounds were weak or negative in the standard mutagenicity assays and Ni(II) ions do not
react with DNA. Consequently, Ni is commonly described as a nongenotoxic carcinogen. However, Ni-
treated cultured cells and lymphocytes from Ni-exposed workers have consistently shown the presence
of chromosomal rearrangements that typically originate from DNA double-strand breaks (DSBs). Also
contradicting its nongenotoxic description is the ability of Ni(II) to cause covalent DNA-protein crosslinks
(DPCs) in experimental animals and in occupationally exposed individuals. The presence of
chromosomal abnormalities and DPCs despite the apparent lack of mutagenicity and DNA reactivity
suggests that Ni may engage some unusual genotoxicity mechanisms. Based on extensive preliminary
results, this project is designed to investigate a novel hypothesis that Ni(II) causes DSBs, DPCs, and
cell transformation by inducing genotoxic topoisomerase I-DNA products. The proposed studies will
determine (1) mechanisms of Ni(II)-induced defects in homologous recombination repair of DSBs, (2)
the importance of error-prone DSB repair in the production of oncogenic genetic changes by Ni(II), and
(3) formation and pathophysiological significance of Ni-induced topoisomerase I-containing DPCs and
DNA breaks. The completion of this work is expected to uncover molecular mechanisms of the
formation of oncogenic genetic abnormalities by a nonmutagenic carcinogen Ni and identify novel
biomarkers of DNA damage by this metal.

## Key facts

- **NIH application ID:** 10757664
- **Project number:** 5R01ES031979-04
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Anatoly Zhitkovich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $358,875
- **Award type:** 5
- **Project period:** 2021-03-18 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10757664

## Citation

> US National Institutes of Health, RePORTER application 10757664, Nickel and toxic topoisomerase I products (5R01ES031979-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10757664. Licensed CC0.

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