The control of genome integrity and their importance for the cell

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Published: 23 Jul 2015
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Dr Marco Foiani - Scientific Director, IFOM, Milan, Italy

Dr Foiani talks to ecancertv at IFOM EMBL about his study of the mechanisms which control chromosome integrity which in turn prevent genome instability and their pivotal importance for the cell. 

Our laboratory studied a mechanism that controls chromosome integrity and therefore that prevents genome instability which is a problem in all cancer cells because it has a causative role in tumour formation and development as well as the relapse of two chemotherapeutic agents.

For many years we have been studying the mechanisms and regulatory pathways.

In particular we have studied a mechanism that couples chromosome replication with DNA repair recombination.

Basically what we did was to induce DNA damage in a space and study all those processes that maintained a conformational replication, preventing aberrant transitions.

More recently we are interested in trying to understand which is the essential role of the so-called DNA damage response kinases, in particular ATR which is a PI3 kinase and particularly to try to understand which are the essential physiological functions of this kinase.

It turns out that a key role of these proteins is to co-ordinate the clash between transcription and replication which is a big challenge for the cell, lots of things may go wrong.

So basically the way I see it is like two trains that crash head-on on the same track.

We believe that this is a huge problem for oncogenes because oncogenes induce the so-called replication stress which is likely due to an unscheduled transcription event in their space.

So the co-ordination of this event is crucial for the cell and when something goes wrong we have a tremendous combination of DNA damage.

A question that we are trying to address more recently these days is which are the sensing mechanisms that allow the cells to be able to monitor and to sense the clash between replication focussed transcription units.

It turns out that recent data obtained in our laboratory really suggests that the cell is able to sense the mechanical forces which are generated by chromosome dynamics at the nuclear envelope not only during chromosome replication but also during condensation.

ATR plays a huge role here because it acts as a mechano-sensor.

In fact, we did open a new field here because this kind of process really couples chromosome dynamics with nuclear envelope metabolism and mechanotransduction pathways acting inside and outside the nucleus.

There’s another line of research in the lab which is more involved in trying to understand which are the connections between the metabolic processes and the DNA damage response and chromosome integrity.

In particular we are studying the links between the main PI3 kinases, mTOR, ATI and ATM.