Faculty Profile: Anatoly Zhitkovich, PHD

Anatoly Zhitkovich
Anatoly Zhitkovich, PHD
Professor of Medical Science
Pathology & Laboratory Medicine
Work: +1 401-863-2912
We study cellular stress responses that control activity of accurate and mutagenic DNA repair processes and cell fate decisions following DNA damage by carcinogenic chemicals and anticancer drugs.

Institutions

Bu

Research Description

Research Theme: DNA repair, DNA damage and stress signaling

DNA is the principal target of the vast majority of human carcinogens. These genotoxic chemicals initiate the carcinogenic process by causing DNA damage that subsequently generates mutations through erroneous replication. DNA is also the main target of several classes of chemotherapeutic drugs that exploit the vulnerability of cancer cells to certain forms of DNA damage. It has recently become evident that the amount of the initial DNA damage is not always predictive of the biological consequences, such as cancer risk among exposed individuals or efficacy of chemotherapy. There are numerous cases when cancer cells acquire resistance to drugs without any decrease in the amount of drug-induced DNA damage.

Our main research efforts are directed at the characterization of biochemical and genetic factors that regulate resistance to DNA damage-induced cell death and susceptibility to mutagenesis. We are focused on:
(1) DNA damage surveillance mechanisms and their linkage to DNA repair, cellular signaling networks and cell cycle checkpoints. We are particularly interested in the role of mismatch repair proteins as sensors of DNA damage causing activation of stress responses.
(2) Mechanisms of cell death triggered by DNA-targeting anticancer drugs. One of our areas of interests is the determination of the differences in cell death programs between normal and cancer cells and exploitation of these differences in the optimization of anticancer therapy.

We are interested in two classes of DNA-reactive compounds:
(1) Metal complexes containing chromium (Cr) or platinum (Pt). Hexavalent Cr is a major environmental and occupational carcinogen with widespread human exposure due to its large-scale use in metal alloys and inorganic paints. Pt-based compounds, such as cisplatin and carboplatin, are the most commonly used class of drugs in cancer chemotherapy.

(2) Agents that cause covalent DNA-protein crosslinks. DNA protein crosslinking can be caused by endogenous and exogenous aldehydes (formaldehyde, acetaldehyde and others), as well as by bifunctional anticancer drugs (platinum-based drugs, mitomycin C and others). The biological role of DNA-protein crosslinks is poorly understood relative to smaller forms of DNA damage but these superbulky lesions are likely to act as potent inducers of large chromosomal rearrangements and cellular senescence (permanent growth arrest). Induction of a senescent state in cancer cells will terminate tumor growth whereas age-associated accumulation of senescence-promoting DNA-protein crosslinks can contribute to tissue aging and age-associated increases in cancer incidence.

Grants and Awards

Manning Assistant Professor (2000)
Dean's Teaching Excellence Award (2004,2006, 2007, 2008)
Certificate of Recognition for Exemplary Teaching (2009)
Nelson Fausto Teaching Award (2009, inaugural award)
Dean's Excellence in Teaching Award (2010)
Certificate of Recognition for Exemplary Teaching (2011)
Dean's Excellence in Teaching Award (2012)

Affiliations

American Association for Advancement of Science
American Association for Cancer Research
American Chemical Society
Environmental Mutagenesis and Genomics Society
Society of Toxicology

Funded Research

1) NIH R01 ES020689 "Formaldehyde Genotoxicity"
2) NIH R01 ES008786 "Genotoxicity of Chromium Compounds"
3) NIH Superfund Research Program P42 ES013660,
Research Project #4: "Biological Dosimetry of Hexavalent Chromium"

Teaching Experience

BIOL 1290 Cancer Biology (graduate and undergraduate students)
BIOL 2840E Topics in Cancer Biology (graduate seminar)
BIOL 3640, section on Radiation Injury (medical students)

Courses Taught

  • Cancer Biology (BI0129)
  • Topics in Cancer Biology (BIOL2840E)