February 08, 2022

Welcome to the February session!

We are excited to host two great talks this month:

Causes and consequences of DNA replication stress

Vincenzo Costanzo, MD, PhD

IFOM, Italy

How do cells count centrosomes? Novel insights in the p53 pathway

Luca Fava, PhD

CIBIO, University of Trento, Italy

Chairs of the session will be:

About the speaker: Vincenzo Costanzo

Vincenzo Costanzo

Following the award of the medical doctor degree in July 1998 I worked as research scientist at Columbia University, department of Genetics and Development in the group of Dr Jean Gautier from July 2000 to July 2004 as PhD student first and then as postdoc. During this time, I established a vertebrate cell-free system based on Xenopus laevis eggs extracts that recapitulates all the aspects of the DNA damage response, including the DNA damage checkpoint and the activation of DNA repair. Using this system I identified novel DNA damage checkpoints that prevent initiation of DNA replication following DNA damage. I showed for the first time that ATM was bound to DNA containing double strand breaks and that RPA was required for ATR activation in vivo. I then identified a novel function for Mre11 that accounts for its essential role in vertebrates showing that Mre11 is required to yield normal replication products in the absence of apparent DNA damage. These studies established a critical connection between DNA repair and DNA replication in vertebrate organisms. Following the postdoctoral work, I was offered a position at the prestigious Clare Hall Laboratories as a tenure-track group leader where I established the Genome Stability Laboratory in October 2004. I worked on the function of the Mre11 complex and Rad51 in DNA repair and DNA replication.
Here I made a seminal discovery demonstrating for the first time that Mre11 promotes degradation of nascent strands and that Rad51 limits this processing. This novel function of RAD51 has been found to be critical to prevent genome instability and occurrence of chemo-resistance in cancer cells. At Clare Hall I produced several other papers on the identification of new regulators of cell cycle such as Cep63 and Gemc1 and the role of Plk1 and ATM/ATR in promoting DNA replication fork stability.
I also demonstrated for the first time that ATM regulates the pentose phosphate pathway promoting the formation of antioxidant molecules such as NADPH and nucleotide precursors required for DNA repair. This finding established for the first time a direct link between DNA repair and checkpoint genes defective in cancer in cellular metabolism. Following my transfer to IFOM, I reconstituted for the first time the replication, the protein composition and the structure of the chromatin associated to human centromeres, showing that repetitive DNA suppresses ATR activation and visualizing for the first time chromosome DNA loops by EM. More recently I have established the molecular function of SMARCAL1 protein showing that SMARCAL1 induces extensive nascent DNA degradation in the absence of BRCA2 and RAD51 mediated fork protection. Finally, I contributed to define the molecular mechanisms of cohesion association to chromosomes and uncover the role of SAMHD1 in promoting exonuclease activity of Mre11 at stalled forks.
My work over the years has been highlighted in several News and Views and review articles and has led to major advance in the field of DNA damage response and DNA damage checkpoint as confirmed by work from many labs that extended my initial observations to mammalian model systems. During this time, I received numerous invitation to speak at international conferences. In 2010 I was granted a tenured position as senior group leader in UK. My former postdocs and students have achieved independent careers as assistant professors, senior scientist at pharmaceutical companies and prestigious laboratories. I have been awarded the Lister Institute Research Prize, the Harvard-Armenise career development award, European Research Council grant in 2006 and in 2013 and I have been nominated EMBO Young Investigator.

About the speaker: Luca Fava

Luca Fava

Luca Fava is associate professor at the CIBIO, University of Trento, Italy. Following his undergraduate studies at the University of Padova, Italy, Luca took up a PhD position with Dr. Erich Nigg at the MPI of Biochemistry in Munich, Germany, where he studied the spindle assembly checkpoint. During his subsequent postdoctoral appointment in the lab of Dr. Andreas Villunger in Innsbruck, Austria, he focused on the stress signalling pathways that are activated when cell division is not completed faithfully, also laying also the foundation for the projects that he launched as independent PI in Trento.
In the last years at the CIBIO Luca’s group is exploiting a broad range of methods to address the contribution of the centrosome to diverse cellular signalling pathways. While the centrosome has been viewed as a structural component of the cell, their work is beginning to uncover its contribution as signalling centre. Considering that malfunction of the cascades modulated by the centrosome have relevant impact on human health, contributing to the aetiology of cancer, neurodevelopmental and bleeding disorders, their work is acquiring broad medical implications.

About GiiN webinar series

The first GiiN Webinars Series (2021-2022) happens every second Tuesday of the month. It covers latest cutting-edge research in the field of genome stability from two scientists working either in the Italian territory or abroad. This series operates under the kind patronage of AIRC Italian Foundation for Cancer Research.

For more information, to volunteer or to be added to our mailing list, contact us at genomeintegrityitaly@gmail.com