All cells have a capability to propagate themselves. Before they can divide, cells must first duplicate the genetic information with great accuracy. This process is made possible by a highly coordinated structure, known as the replication fork. The replication fork has to copy the genome in a timely and accurate manner. Failure to do so can have deleterious outcomes, such as mutations, DNA damage and/or chromosomal rearrangements. Any condition, which compromises the function of the replication fork is generally referred to as replication stress. For example, ultra violet irradiation or genotoxic chemicals can damage the template DNA strands and introduce replication stress when cells are copying their DNA. Similarly, uncontrolled proliferation in cancer cells also exerts stress on the replication machinery. Replication stress is often a prelude to genome instability and cancer. It is also a “chronic” condition symptomatic for many cancer cells. This suggests that cells, especially those that are cancerous, can manage replication stress to a certain degree. Previous research suggests that cells can keep on proliferating in the presence of replication stress, if the damage is within the limit of cells’ ability to repair. However, if the damage is beyond repair, cells must undergo death to prevent propagation of a faulty genome. Much less is understood how the fine line between tolerance and cell death decision is determined.
My research interest lies in the regulation of specific post-translational modifications (PTM), namely ubiquitin and SUMO (small ubiquitin like modifier), when replication stress ensues. Previous work has shown that these PTMs influence the balance between replication stress tolerance and cell death. Using biochemistry, bioinformatics, genetics and molecular biology, I aim to further under the mechanisms which defy replication stress and the role of ubiquitin/SUMO axis in this context. I use Saccharomyces cerevisiae (budding yeast), an organism highly amenable for genetic manipulation, and also plan to use mammalian cell culture system to address my research questions. Elucidating these processes will bring us one step closer to understanding how cancer cells live with constant replication stress and genome instability, thus revealing the “Achilles’ heel” of cancer.