Cancer is a complex disease caused by interactions of multiple factors, such as genetic predisposition, environmental and lifestyle influences, infectious agents and ageing. Due to the complexity of this pathology, cancer research includes basic research, strategies for prevention, development of early diagnostic tools, and translational approaches for treatment and cure.
In basic cancer research ‘knowledge’ is the key word because if you want to interfere with a biological system you must know how it works. For this reason, the main purpose of this project is to gain information about the mitochondrial form of a DNA repair protein.
Radiation therapy and chemotherapy are the mainstream options available for cancer treatment. Many chemotherapeutic drugs act by damaging DNA, leading to an accumulation of lesions that ultimately cause cell death. However, human cells have the ability to repair damages induced by chemotherapeutics drugs therefore vinifying their effects. Base excision repair (BER) is a cellular pathway able to repair the damage generated at nuclear and mitochondrial DNA. An essential protein for the correct functioning of this pathway is APE1. This protein is present both in the nucleus and the mitochondria, represents a key enzyme of the BER pathway and elevated expression levels have been reported in several carcinomas contributing to resistance to chemotherapy.
Current approaches to cancer treatment report more effective results when specific DNA repair inhibitors are used in combination with DNA damaging drugs. The foremost rationale of the combined therapy is that the repair of DNA is likely to sensitize cancer cells to chemotherapeutic agents.
For this reason APE1 inhibitors are currently in use in therapy as adjuvants to chemotherapeutic drugs. However, an alternative approach to inhibit APE1’s DNA repair function consists in blocking its mitochondrial translocation to alter the ability of the cell to repair DNA damage induced by chemotherapeutic agents. Research activities in this project allowed us to demonstrate, for the first time, the role of the TIM23 channel and the PAM motor complex in the translocation of APE1 into the mitochondrial matrix where the mitochondrial DNA is located.
Moreover, we measured the kinetics of translocation, or in other words, how fast the protein is imported after induction of DNA damage. Our data proved that it takes less than 30 minutes for APE1 to be efficiently imported into the mitochondrial matrix to repair damaged DNA.
This study significantly contributes to filling the knowledge gap about the mitochondrial nature of APE1 protein therefore opening the possibility for further translational approaches to cancer treatment that rely on APE1 protein as a target.
How did you benefit from the POLONEZ fellowship?
Polonez has been a life-changing experience. The fellowship gave me the possibility to work for two years in an internationally renowned Polish research institute while pursuing my scientific interests through a basic research project. During this period I had the possibility to improve my knowledge of mitochondrial biology, strengthen my collaboration with my host, Prof. Chacińska, and establish new collaborations with Polish scientists. I was the recipient of the fellowship but not the only beneficiary of the project – four of my Italian collaborators also had an opportunity to spend some months with me at the Centre of New Technologies of the University of Warsaw.
But the fellowship impacted not only my profession, but also my family. Indeed, I came to Poland with my wife Elena and our five-year-old daughter Alice. She attended the International Preschool of Warsaw where I organised a laboratory experience to show the kids that bacteria are on our hands and why it is important to wash our hands before eating to remove bacteria.
POLONEZ was an unforgettable life experience: we fell in love with Warsaw and I really hope to be able to come back to Poland!
Dr Carlo Vascotto is Assistant Professor of Molecular Biology at the University of Udine in Italy. His research interests are focused on the understanding of some basic molecular mechanisms of cancer, in particular the mechanisms responsible for repairing damaged nuclear and mitochondrial DNA, and the role of mitochondria in tumorigenesis, tumour progression and resistance. He also positively contributes to students’ and junior faculty’s careers by mentoring and teaching Molecular Biology.
His scientific collaboration with Poland dates back to 2015 when he was a guest of the Mitochondrial Biogenesis laboratory headed by Prof. Agnieszka Chacińska at the International Institute for Molecular and Cell Biology. POLONEZ allowed him to work for two years at the Centre of New Technologies of the University of Warsaw. He continues to collaborate in different research projects with other Polish scientists.