Hello! I'm Nick Sillett and I'm currently an Early Career Fellow with the Institute of Advanced Studies funded by the MRC.
In 2011 I began a three year Medical Biochemistry (BSc) degree at the University of Leicester. I studied a wide range of topics, most were biochemistry based but I also elected to focus a large portion of my degree on genetics. My final year dissertation project was spent researching proteins involved in inducing senescence, a physiological process that has been implicated in the symptoms of human ageing. I graduated in the summer of 2014 with a first class honours degree as well as being awarded the Medical Biochemistry prize for the best experimental dissertation project of that year.
In the summer of 2013, I spent time working in Daniel Fisher's cell cycle lab in Montpellier. Throughout my stay I assisted the ongoing research of Vjekoslav Dulic, and during the process I learnt a whole host of laboratory techniques which stood me in good stead to tackle my upcoming dissertation project.
After my undergraduate study, I was accepted onto the Interdisciplinary Biomedical Research course funded by the MRC as part of their doctoral training partnership here at Warwick. This was a four year programme consisting of an initial MSc course followed by a 3 year PhD. I began the MSc year of my course in late September 2014, which focused on building a skillset with which I could meet the demands of modern scientific research. This involved learning diverse topics such as large scale data analysis, modern microscopic techniques, complex mathematical modelling and statistical analysis, as well as many others.
The latter half of my MSc year was spent doing two 12 week placements in different labs at the university. I spent the first working with Giacomo de Piccoli in the Medical School, which was titled: "Utilising a 2-step IP Method to Investigate Post-Translational Modification of the Yeast Replication Complex". This was a primarily biochemical project, in which I attempted to purify the machinery that replicates DNA in budding yeast. This was so I could examine any potential post-translational modifications that occurred when replication stress was induced.
My second project was spent in Andrew McAinsh's lab in the Mechanochemical Cell Biology Building where I worked using quantitative immunofluorescence techniques to assess the function of kinetochore proteins. The project was titled: "The identification of a possible Ndc80-like microtubule binding domain on CENP-Q" and, using the techniques mentioned earlier, was focused on investigating the function a structural part of a kinetochore protein that was played a role in aligning chromosomes to the cell's equator as it divides. I graduated in September 2015 with a distinction.
PhD and Current Research
I started my PhD in October 2015 under the supervision of Giacomo De Piccoli. As cells divide, they first must replicate their entire genome during the S phase of the cell cycle. Every base of the genome must be accurately duplicated and this is carried out by the piece of cellular machinery known as the replisome. In its simplest terms, this is formed of a helicase, which unwinds the two strands of DNA, and three polymerase complexes, which synthesise new DNA duplexes by adding complementary bases to those present on the unwound single strand. This complex must also be able to respond to the many factors which can disrupt this process, collectively termed replication stresses. These can range from physical blockages that impede the progression of replisomes to sites damaged DNA, like those caused by ultraviolet light exposure. The cell has evolved numerous pathways which can detect these stresses, either signalled by the replisome or at distant sites, and pause replication until these are removed and repaired. Failures in responding to replication stress can give rise to an assortment of mutations and genome instability, which can drive the transformation of a healthy cell to a cancerous one.
During my research, I used the model organism Saccharomyces cerevisiae, commonly known as budding yeast, as many of its components that carry out DNA replication have exact counterparts in our cells, ensuring research is transferable to human systems. My work focused on examining the diverse roles DNA Polymerase ε plays during chromosome duplication. I showed that the enzymatic component of this complex, Pol2, not only allows it to carry out DNA synthesis, but also appears to play a crucial role in initiating this process in origin firing, stimulating the progression of the replisome as it replicates DNA as well as a previously unknown function in signalling DNA damage.
Over the course of my PhD I was given ample opportunity to present my work, including a presentation at the joint MRC-DTP conference hosted by Kings College London and Warwick University, as well as a poster at the 'DNA Replication: From Basic Biology to Disease' conference hosted by EMBL in Heidelberg, Germany. After submitting my thesis in September 2018, I was accepted as an MRC-DTP Early Career Fellow. During the 6 month period of my fellowship, I hope to finish off some of the work performed as part of my PhD and publish it in a high-profile journal. With the Institute of Advanced Studies, I hope to develop my portfolio of skills to put me in a place that will allow me take the next step in my career.
N dot Sillett at warwick dot ac dot uk