Understanding the role of PrimPol in damage tolerance during genome replication in eukaryotic cells

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Our cells contain DNA, the so called "genetic blueprint of life", which encodes the information for all our genes. DNA has a simple repeating structure composed of two complementary strands of DNA, which form long, string-like, double-helix structures that make up the genome. Our genome is packaged away into chromosomes, contained in the nucleus of nearly every cell, which must be copied as cells divide to produce daughter cells. Cells produce a large number of proteins responsible for "photocopying" this DNA blueprint. The proteins tasked with accurately copying the several billion letters of our genetic code are called DNA replication polymerases. During this copying process the replication machinery is frequently stopped by damaged DNA and this can lead to failure to replicate or the production of mutations to the sequence of the DNA that can, eventually, lead to the development of disease states, such as cancer. Fortunately, our cells produce damage tolerance proteins whose role it is to prevent this from occurring or restart replication when it stalls. We have recently discovered a novel human lesion bypass polymerase in human cells called PrimPol and shown that this protein, together with other cellular factors, plays an important role in helping the cell's replication machinery to bypass DNA damage it encounters during every round of cell division thus ensuring efficient genome replication. In particular, we have shown that loss of PrimPol leads to replication slowing, particularly past lesions produced by UV light, suggestive that it is required for efficient replication through these kinds of DNA damage. In this programme, we are proposing to identify how these molecular machines are able to bypass DNA damage, what are the cellular and organismal consequences of deletion or mutations in this gene (e.g. diseases associations) and, finally, how does PrimPol co-operate with other bypass proteins to ensure that replication proceeds in a faithful and complete fashion.The accumulation of mutations can lead to uncontrolled cell growth that leads to the development of diseases, such as cancer. It is therefore important to understand how cells respond when the replication machinery stops at sites of damage. An "Achilles heel" of cancer cells is that they grow more rapidly than other cells in our body and thus they replicate their DNA more often. Because of this, many cancer treatments deliberately introduce damage to DNA replication in order to selectively slow/kill cancer cells. We hope that, by understanding how the replication machinery tolerates such damage, we may be able to increase the efficiency of cancer treatments by finding ways of making cancer cells even more likely to be killed by drugs that block DNA replication.