PI3K-Like Protein Kinases
Connections between DNA-PK, ATM, ATR and mTOR dependent pathways
Prof Marco Foiani - Scientific director, IFOM, Milan
PI3 kinases are very interesting enzymes that control a variety of several processes, that includes DNA damage response, signal transduction and nutrient-sensing pathways. It’s clear that most of these PI3 kinases, such as ATR, ATM, mTOR and DNA–PK, are quite similar which suggests that they might work with a similar mechanism. Therefore the idea of this meeting comes from people like me; I work on DNA damage response but I want to learn how ATR is working and perhaps I will learn a lot by listening to other scientists working on different fields, maybe studying the mechanism of action of TOR.
So the idea is to generate a cross-fertilisation between different fields so that each of us can learn from the other one. At the end, each of us mostly focuses in our own field so we attend our meetings but it’s becoming clear that each field, like DNA damage response, signal transduction, nutrient-sensing fields are becoming mature enough to share a common audience. That’s the idea. I’m sure each of us will benefit by this interdisciplinary context.
How does your personal research fit with the meeting?
Years ago we published this paper in which we connected the autophagic pathway with DNA damage response. We found that every time that autophagy is triggered some key factors activating the DNA damage response become limiting. From that I suspected that maybe there was a cross-talk between the ATR pathway working in the nucleus controlling the DNA damage response and the mTOR pathway which controls autophagy, which is working outside the nucleus. So we published that but we collected lots of evidence in support of this connection which is becoming very, very intriguing. In fact, we have two stories that link ATR and ATM dependent DNA damage response pathways with non-nuclear events controlled by mTOR which comes in two flavours, one is TORC1 and one is TORC2. Both these complexes seem to interfere, influence, the DNA damage response.
What are your most recent findings?
Most of us studying the DNA damage response try to address the signal transduction events occurring in laboratory conditions when cells are spoiled by media and by the fact that they are very young cells. So we learn a lot but it’s becoming clear, at least to us, that all cells, and particularly cells which are experiencing chronological aging, behave differently. So what we found is that the DNA damage response pathway is limiting in all cells but we can rescue this kind of cripple activation pharmacologically genetically and this is, in fact, what is going to be the story I’m going to discuss at this meeting. The endpoint of the story is that there’s a strong connection between nutrient-sensing pathways, again the mTOR dependent pathway, and ATR. In particular we understand now that in all cells there are some key metabolic processes which influence the activation of the DNA damage response. I suspect that it might also be the other way around, that is that certain DNA-PK also affect metabolism, certainly this is the case, we’ve got other speakers who will speak about this. But now our main focus is on all cells.
