Dr. Haber discusses how normal cells deal with DNA damage and genomic integrity; and how those systems go awry in cancer cells.
Epigenetics: Damage Control in the Cell
Well, I work in an area of DNA repair. And what we have come to realize over the last decade is how these repair mechanisms prevent cells from becoming cancerous. Every time– well, this is a good number. In your lifetime, you make a light-year’s worth of DNA. And in virtually every cell of your body, the DNA is still arranged exactly as it was in the time that you became a fertilized egg. And therefore every time the cell has replicated, its genome has managed to preserve its order.
Cancer cells have lost that. They’re frequently characterized by many, many rearrangements of sequences, two segments having been broken and joined together. And all of those kinds of things like that, these translocations and other rearrangements, they only arise when the cell fails to do its normal levels of repair.
So we study the normal repair mechanisms that are designed to prevent cancer-like events from happening. So there’s been a tremendous insight into this process by all the new molecular biological technology that makes it possible to do things we couldn’t do even a decade before.
And one of the things that excites me is that we have learned that although the repair process is very accurate, it actually comes at a cost. And the cost is an increased level of mutagenesis. And the kinds of mutations that we have encountered in a simple organism– we study budding yeast which in no way is a cancer cell– nevertheless, the kinds of mutations we see have now been seen by the deep sequencing methods that are available in characterizing breast cancer cells and other cells. So we think that the way we’re studying it in this model organism is applicable to understanding the origins of these kinds of changes in big cells, in human cells.
I mean some things are very basic. We know that after DNA damage, the cell responds to it by alarming what’s called the DNA damage checkpoint. It causes cells to stop and not to go through mitosis. We assume that’s so that it gives the cell more time to do the repair. And then after the repair is over, it turns this machinery off and it resumes cell cycle progression.
There are still fundamental questions about how exactly the cell knows that there’s damage. And there are even more fundamental questions about understanding how the cell can turn off this alarm after it has turned it on. How does it know that the repair is over?
And one of the things that I talked about today, that we for the first time have a handle on, is a system where we can watch the chromatin be put back together after the DNA repair is over. And I’m hoping that in a relatively short time, we can understand what chromatin chaperones and remodelers and other proteins are necessary to reestablish the DNA back to its original state after it had suffered a break, and found a template, repaired the break. And then this naked piece of DNA has to get put back into a intact piece of functional chromatin. And I think some of those things we’ll be able to answer in a year, if not six months.