Tahir H Tahirov
University of Nebraska Medical Center, USA
Title: Unraveling the puzzles of human DNA replication
Biography
Biography: Tahir H Tahirov
Abstract
All eukaryotes possess four paralogous B family DNA polymerases: Pola, Pold, Pole and Polz. Pola functions in initiation and early elongation steps of replication. Pola 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. Pold plays a central role in DNA replication and DNA repair in eukaryotic cells. Pole is involved in the initiation of replication at origins and in leading-strand synthesis in the vicinity of the origins, whereas Polz is involved in translesion DNA synthesis. When Pold encounters replication-blocking lesions, it switches from replication to translesion synthesis by recruiting damage bypass polymerases, including Polz. Polz is responsible for nearly all mutations induced by DNA damaging agents in human cells and model organisms. Accumulation of mutations in cellular genetic material causes various diseases, including cancer.In spite of key role of B family DNA polymerases in replication and genome maintenance, only limited data are available regarding mechanisms of their functions. Our aim is to explore the structural features beyond the polymerase catalytic core and reveal how the intersubunit interactions and conformational changes regulate the function of these polymerases. We started with crystal structure-based characterization of the role of the second B-subunits in human B-family DNA polymerases. In particular, we determined the crystal structures of B-subunit complexes for all four DNA polymerases and discovered that Pold and Polz are sharing the same second and third subunits. We will briefly review our recent achievements and focus our presentation on novel crystal structure of entire human primase-Pola complex. The structure reveals how the primase and Pola are acting in a highly coordinated fashion during the initiation of RNA primer synthesis, extension and counting by primase and transfer of primer-template duplex for further extension by Pola.