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. Eukaryotes possess four B-family DNA polymerases, Pol alpha, Pol epsilon, Pol delta and Pol zeta. Pol alpha functions in initiation and early elongation steps of replication. Pol alpha is tightly associated with a primase and hence is the only DNA polymerase that can initiate the synthesis of DNA by extending RNA primers laid by primase. Pol alpha and Pol delta are involved in accurate and efficient replication of chromosomal DNA. Contrary, Pol zeta is responsible for nearly all mutations induced by DNA damaging agents in human cells and model organisms. Inactivation of any of those polymerases is lethal, while the diminished or inappropriate activity leads to mutations and chromosomal abnormalities, the known cause of cancer. Although the structure of the catalytic domains are known, the lack of information of the structure of the polymerase accessory subunits precludes the understanding the mechanisms of leading and lagging DNA strand synthesis, as well as the mechanisms of switch from accurate replication mode to DNA repair mode. The availability of structural information on all subunits of eukaryotic B family polymerases and interactions within the subunits will radically change the understanding of the processes leading to mutagenesis and cancer and will create a platform for the design of chemicals regulating cell mutability.
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