Elucidating how the PrimPol DNA damage tolerance pathway is regulated and where it operates in human cells

Cells produce enzymes called DNA polymerases responsible for "photocopying" the genome, which encodes the cell's biological blueprint. Polymerases are frequently stalled by genetic obstacles caused by DNA damage or structures on the template being replicated, leading to defective DNA copying or the formation of mutations that can lead to diseases, such as cancer. We have identified a damage tolerance protein called PrimPol, whose role it is to restart stalled replication by repriming DNA synthesis downstream of obstacles encountered on the genome. We are proposing to identify how and when PrimPol, and its partners, localise to sites of stalled replication, how this process is regulated and deregulated, where on the genome this repriming mechanism performs its roles and, finally, how PrimPol co-operates with other restart mechanisms in the cell to ensure that replication proceeds in an efficient way. Understanding how the replication machinery tolerates such genetic obstacles in human cells will advance the development of more efficiency inhibitors that block genome duplication in cancer cells.