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Zhang Lab

Molecular Mechanisms of DNA Repair and its Role in Cancer Development

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Investigator / Contact Person Yanbin Zhang

Research

To deal with various genomic stresses, cells developed fascinating DNA repair pathways. These repair pathways safeguard genome from almost all unfavorable DNA modifications that initiate cancers and other human diseases. Our laboratory is interested in DNA interstrand cross-link (ICL) repair. ICLs are among the most toxic DNA lesions, since they covalently tether both duplex DNA strands and prevent essential DNA metabolic functions such as replication and transcription. Deficient ICL repair underlies the chromosomal instability and the hypersensitivity to DNA cross-linking agents in the cancer-prone syndromes such as Fanconi anemia, some of hereditary breast and ovarian cancers, and xeroderma pigmentosum.

Yet, induction of ICLs is a proven strategy for the treatment of cancers and hyperproliferative disorders. It appears that ICLs represent the primary cytotoxic lesion induced by most bifunctional alkylating agents. Many clinically important cancer chemotherapeutic agents (MMC, cisplatin, psoralen, nitrogen mustard, nitrosourea and etc) are bifunctional alkylating reagents that react with both strands of the DNA helix, produce ICLs, block replication and transcription, and induce apoptosis in tumor cells. Cells can acquire resistance to such agents by repairing or tolerating these ICLs. Understanding how cells repair and tolerate ICLs will greatly facilitate the development of strategies to cure the cancer-prone diseases and to prevent drug resistance. Our laboratory is interested in decoding the mechanism of ICL repair and the specific functions of Fanconi anemia proteins, nucleotide excision repair proteins, translesion synthesis proteins, homologous recombination proteins, and ubiquitination proteins in this complex repair pathway. Our study relies on the in vitro reconstituted system with purified proteins and defined DNA substrates, and the in vivo cell biological tools.