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

细胞产生一种名为DNA聚合酶的酶，负责“影印”基因组，基因组编码细胞的生物蓝图。聚合酶经常因DNA损伤或模板结构被复制而引起的遗传障碍而停滞不前，导致DNA复制缺陷或形成突变，从而导致疾病，如癌症。我们已经确定了一种名为PrimPol的损伤耐受蛋白，它的作用是通过在基因组上遇到障碍的下游重新启动DNA合成来重新启动停滞的复制。我们建议确定PrimPol及其合作伙伴如何以及何时定位于停滞复制的位置，这一过程是如何调节和解除调节的，这种重新启动机制在基因组的哪里发挥其作用，最后，PrimPol如何与细胞中的其他重新启动机制合作，以确保复制以有效的方式进行。了解复制机制如何耐受人类细胞中的这种遗传障碍，将推动开发更有效的抑制肿瘤细胞基因组复制的药物。

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.