This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Carcinogenesis and anti-cancer drug resistance are major focuses of cancer research. Both processes are associated with a newly identified DNA polymerase family, the Y family. Y-family polymerases are main players in translesion (DNA damage bypass) DNA synthesis, which are characterized by their ability to replicate transverse lesions and by their reduced fidelity in DNA replication. Due to their mutagenic potential, Y-family polymerase activities must be tightly regulated. It has been demonstrated that sliding clamp proteins (PCNA) play an important role for the regulation. Benzo[a]pyrene (BP) is a ubiquitous environmental pollutant and a carcinogen. The BP-adducts in DNA cause elevated mutagenesis in cells and leads to a variety of cancers. It is the Y-family polymerases that make extra mutations when they replicate past lesions erroneously. Cisplatin is one of the most widely used chemotherapeutic drugs for human cancers. However, intrinsic or acquired resistance to cisplatin constitutes a major limitation in its application. Cisplatin exerts its cytotoxicity through the formation of covalent adducts in DNA. These adducts inhibit DNA synthesis in rapidly dividing tumor cells. Lesion bypass replication causes drug-resistance to cisplatin in cells, which are mainly performed by Y-family polymerases. We use Y-family polymerase Dpo4 as an in vitro system and to explore the structural details of how the Y-polymerase interacts with PCNA proteins, BP- & cisplatin- DNA adducts that are closely associated with cancers and cancer treatment. The structural analysis will reveal specific interactions of PCNA with translesion polymerases. Knowledge of the detailed interactions between the protein and lesion substrates will help to understand the damage-induced mutagenesis and provide a molecular basis for DNA damage tolerance that renders cisplatin resistance in cancer treatment. The results will be invaluable in rational drug design to treat cancer.
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