During the last grant period, Dr. McHenry made important progress in identifying the key communication circuits that permit communication between components of the replisome during DNA replication at coupled duplex replication forks. A centrally important player that emerged was the tau subunit of the DNA polymerase III holoenzyme. Tau is the key organizing subunit that links the leading and lagging strand polymerase; it couples the holoenzyme with the DnaB helicase at the replication fork, providing a potential communication circuit with the primase that associates with DnaB; it protects the beta sliding clamp processivity factor from premature removal by exogenous gamma-complex and it plays a key role in determining the fidelity of DNA replication. In the next grant period, he will address the central issues of replication fork communication and dynamics with a primary focus on the contributions of the important organization and communication links mediated by the tau subunit. The principal investigator will exploit the monomeric C-terminal domains of tau to determine the contribution of the normally multimeric tau protein to the lagging strand polymerase mediated through contacts with the DnaB helicase. He will conduct further tests of the hypothesis that a dimeric tau subunit organizes the replication fork by dimerizing the leading and lagging strand polymerases. Dr. McHenry will determine the importance of replication proteins and replication intermediates in providing the signal for the lagging strand polymerase to dissociate and recycle to nascent primers synthesized at the replication fork. He will determine if there is communication between leading and lagging strand polymerases at the replication fork. He will determine the influence of interaction of DNA polymerase III with holoenzyme auxiliary proteins and primosomal proteins on replication fidelity.
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