Anatoly Zhitkovich
Associate Professor:
Pathology & Laboratory Medicine
Phone: +1 401 863 2912
Anatoly_Zhitkovich@Brown.EDU
Our main research efforts are directed at characterization of molecular mechanisms responsible for cell death and mutagenicity of DNA-reactive carcinogenic chemicals and anticancer drugs.
Interests
Research Theme: DNA repair and stress responses to DNA damage
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 causes of resistance to DNA damage-induced cell death and 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 bifunctional anticancer drugs. The biological role of DNA-protein crosslinks is poorly understood relative to smaller forms of DNA damage but these very bulky lesions can act as highly 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.
Degrees
PHD
Awards
Manning Assistant Professor (2000)
Dean's Teaching Excellence Award (2004,2006, 2007, 2008)
Affiliations
American Association for Advancement of Science
American Association for Cancer Research
American Chemical Society
Environmental Mutagen Society
Society of Toxicology
Teaching
My major teaching responsibilities are in the area of cancer biology (undergraduate and Ph.D. students) and radiation pathology (medical students).
Funded Research
1) NIH R01 ES008786 "Genotoxicity of Chromium Compounds"
2) NIH R01 ES012915 "Sensitivity Mechanisms in Chromium Toxicity"
3) NIH Superfund Research Program Award P42 ES013660,
Research Project #4: "Biological Dosimetry of Hexavalent Chromium".
Curriculum Vitae
Download Anatoly Zhitkovich's Curriculum Vitae in PDF Format
