DNA POLYMERASE ETA/DNA/DNTP COCRYSTALS: A LARGE UNIT CELL PROBLEM

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The survival of all organisms depends critically on the ability to faithfully replicate DNA. Cellular DNA is continually subjected to damaging agents and a variety of DNA repair pathways have evolved to repair the resulting lesions. How cells bypass these lesions during DNA replication has been a key question in the areas of DNA replication, mutagenesis, and carcinogenesis. The answer to this longstanding puzzle came only recently with the discovery of DNA polymerase eta (Pol eta), a prototype of a new family of translesion DNA synthesis (TLS) polymerases. Pol eta is unique amongst eukaryotic DNA polymerases in its proficient ability to replicate through a UV-induced cis-syn cyclobutane thymine-thymine (T-T) dimer by inserting two adenines opposite the dimer. Mutations in human Pol eta are responsible for an inherited cancer-prone disorder, the variant form of xeroderma pigmentosum (XP-V). Pol eta is, thus, the first DNA polymerase demonstrated to act as a tumor suppressor in humans.