Tuesday, February 16, 2010

Local Science: Caspase Activation and Differentiation

This seems to be all over the news this morning, but in case it was missed: researchers at the OHRI, led by Lynn Megeney, have found that caspase-3 induced DNA damage is required for differentiation into muscle fibre. As usual, Ed Yong at Not Exactly Rocket Science has a great summary of the PNAS paper and analysis.
But Larsen has found that stem cells deliberately break their own DNA by recruiting caspase-3 and CAD. This act of self-harm switches on important genes that are needed for differentiation; without it, the generalist cells can't specialise. This is an entirely new way of activating genes and it appears to be both important and widespread. [...] The myoblasts need these breaks to produce muscle fibres and to create the breaks, they rely on caspase-3 and its ability to activate CAD. Larsen managed to block the development of muscle fibres by dousing myoblasts with chemicals that neutralise caspase-3. The same thing happened if he used cells with mutant versions of CAD, which couldn't be activated. In both cases, the cells failed to show any signs of broken DNA.


Anonymous Coward said...

Haven't read the study yet but I've seen his stuff before... It wasn't clear to me how the DNA can be dammaged, and caspase 3 activated but the cells don't die. Seems like a dangerous strategy to damage your own DNA and become insensitive to death signals from a cancer standpoint. That being said I've noticed my Leydig cells activate caspase 3 when they differentiate, i was just never sure if it was a weeding out process or if they eventually recover from it...

Kamel said...

It seems like it's only cut in particular spots in the differentiation process and not widespread slice and dice. They suspect that may be due to DNA conformation. I suppose it's one way to tightly regulate a well-orchestrated process: if the cell screws up these precise cuts, it enters full blown apoptosis?

It does pose some interesting conundrums as you point out - would targeted differentiation in this manner have some weird side effects? What about therapies that target apoptotic processes?

Rob said...

Ed Yong is pretty awesome.
Same here I have heard about this stuff for years now and wondered if I would ever see it published.
I don't see there being a cancer problem. Sure the differentiated muscle cells will possibly be rendered insensitive to death signals but I don't see them replicating with lots of DNA damage. Perhaps they are rendered more sensitive to apoptosis as well.
Pretty neat stuff. AC you should have sent him some of your caspase 3 westerns from your Leydig cells. PNAS isn't too shabby.