Frontiers of science feature: Dr. Roberto Bellelli investigating DNA replication

In this post I’ll be chatting with Dr. Roberto Bellelli. He’s a principal investigator at Barts Cancer Institute, Queen Mary University of London, investigating the mechanisms of DNA replication.

Dr. Roberto Bellelli is interested in the mechanisms of DNA replication and its alteration in cancer. He has published in prominent journals such as Molecular Cell and Cell Reports.

Introduction – what is DNA replication?

It's like making the copy of a document, but instead of paper, it's the DNA molecule that is being copied. During DNA replication, the two strands of the double helix are separated, and each strand serves as a template for the creation of a new complementary strand. The new nucleotides that make up the new strand are added in a specific order by special enzymes called DNA polymerases. This process ensures that the genetic information stored in the DNA is accurately transmitted to the next generation of cells.

DNA replication is a highly regulated process and involves many different proteins and enzymes. It is complex but extremely precise and is essential for the accurate transmission of the genetic information and to prevent the development of errors (or mutations) into the DNA. As such, it is fundamental to prevent both genetic and acquired diseases, such as cancer.

DNA replication in cancer

In cancer, DNA replication can go wrong in several ways. One common way is the DNA replication machinery making mistakes when copying the genetic material; this finally leading to mutations in the DNA sequence. These mutations can disrupt the normal functioning of genes that regulate cell growth and division, leading to uncontrolled cell growth and the development of tumors.

Another way DNA replication can go wrong is secondary to damage to the DNA molecule itself, which can be caused by environmental factors such as radiation or chemicals exposure. This damage can interfere with the normal process of DNA replication, leading to errors or incomplete replication finally resulting in mutations and changes to gene function.

Finally, some cancers may have defects in the genes that are responsible for regulating the dynamics of DNA replication, for example where and when to start it. These defects can lead to abnormal DNA replication and the accumulation of genetic errors.

Overall, DNA replication plays a critical role in the maintenance of genome integrity, and disruptions in this process can lead to the genetic changes that drive cancer initiation and progression.

Featured researcher: Roberto Bellelli, MD PhD

What is your background?

I have a background in medicine and I am particularly interested in genome stability and cancer biology. While studying for my medical degree in Italy, my supervisor proposed me to do a laboratory project in molecular oncology. After my graduation in medicine, I was then asked to enter a PhD program in molecular oncology and endocrinology, and I initially intended to work on a PhD for 3 years only. However, I became so engrossed in the project and basic research that I never looked back. Afterwards, I enjoyed the opportunity of doing a postdoc in the UK to continue my research.

Compared to medicine, I felt that science could offer me a greater sense of challenge and freedom to pursue my interests. That’s why I did not regret pursuing science as a full-time job and career.

How did you get interested in your PhD topic?

During my medical studies, I noticed that many clinical oncologists lacked a critical understanding of the molecular biology of cancer, despite the “explosion” of targeted therapies. As for myself, I was particularly interested, at the time, in targeted therapies and mechanisms of resistance. For my PhD, I chose to study the NCOA4/RET oncogene, which is caused by the fusion of the tyrosine kinase domain of RET, a classic tyrosine kinase receptor and the NCOA4 gene. I took on the challenged to discover the unknown functions of the NCOA4 partner gene by combining mouse genetic and cell biology approaches. This led me to discover that NCOA4 is a novel regulator of both DNA replication and iron metabolism, pointing to a crucial tumour suppressor function.  My PhD studies piqued my interest in the field of DNA replication and genome stability. I was one of the few researchers working on this topic in the whole instutute where I did my PhD, which was very challenging at the beginning.

With this in mind, my PhD supervisor suggested me to spend a summer internship in a genome stability laboratory. Thus, I spent 3 months in the lab of Anindya Dutta in Charlottesville (Virginia, USA) a pioneer in the studies of DNA replication and genome instability in cancer. I had one of the best experiences of my life there. Anindya’s lab was quite diverse and large with almost twenty people coming from everywhere in the world and interested in several aspect of genome stability and cancer biology. Here I got further pulled into fundamental basic biology. Despite all the challenges, I always held the belief that any project could be successful with hard work and perseverance.

What are you currently working on?

We are interested in all the major steps of DNA replication and how the cancer cell hijacks the DNA replication machinery to foster genetic instability. In essence, the whole process from initiation of DNA synthesis to replication fork stability and DNA repair and how this is linked to cancer biology and therapy.

At the moment we are working on the breast cancer susceptibility gene BRCA1, looking into how it protects replication fork in specific chromatin environments and on a specific DNA Polymerase called Pol Epsilon which is frequently altered in human cancer. We use techniques such as DNA fibers, microscopy and classical cell biology. Besides this, we are getting more into biochemistry, including reconstitution experiments with in vitro purified proteins.

How do you envisage the future of DNA replication?

I think the field is moving into reconstituting the DNA replication machinery in vitro but also combining this with cryogenic electron microscopy and single molecule approaches. Additionally, there is a general push to move into genomics, with “genome-wide” characterization of dysfunctional DNA replication by single cell genome sequencing and nanopore sequencing. So, the field will involve efforts of in-depth characterizations from the single molecule to the single genome.

Future projects in my lab will look into how the epigenome is transmitted during DNA replication genome-wide using novel techniques such as the CUT & TAG methods.

Who inspired you in science?

I’ve met many great scientists during my career. At the beginning stages, my PhD supervisor Dr. Massimo Santoro and Dr. Anindya Dutta were a great source of inspiration for their dedication. Later on, my post-doc supervisor Dr. Simon Boulton inspired me a lot on how to successfully progress into an academic career. And, of course all the big players in the fields of cell cycle and genome stability made a lasting impact on me, such as the Nobel prize winners Paul Nurse and Tomas Lindahl, who I had the pleasure of seeing at the Francis Crick institute where I did my post-doctoral work.

When do you get your inspiration for experiments?

Sometimes it is during random moments or looking at data of my PhD student or post-doc, sometimes during a talk or a chat with another scientist. Sometimes it is just after my afternoon espresso.

I think communication with others is essential for this process. It’s important to talk to others, share ideas and collaborate. Most of the times though I have too many ideas and I try to pick the most exciting ones as resources are unfortunately limited.

Do you have one piece of advice for someone starting in science?

Find something that challenges you, so you are always excited and working hard. Never give up. Keep working on it even if you seem stuck, eventually it will pay off.  If you’re not genuinely excited about something, this will unlikely work out.