Unraveling the Function of PAX3-FOXO1’s Activation Domain in Rhabdomyosarcoma
Rhabdomyosarcoma is a childhood cancer that often resurfaces after chemotherapy, making it a challenging disease to tackle. The main culprit is a fusion protein called PAX3-FOXO1 (P3F), which causes the cancer by meddling with our DNA. Imagine this protein as a small machine that tweaks the opening, closing and 3D folding of the DNA instructions in our cells, leading to the growth of cancer. One part of the machine binds DNA, but little is known about the other half of the machine. Our recent research has discovered some new features in this non-DNA binding half, in particular a small 'hook' in an otherwise very floppy part of the P3F protein. We believe that this 'hook' acts like a magnet, pulling in other proteins and molecular tools necessary for P3F to modify DNA.
Two proteins, CBP and p300, are particularly attracted to this 'hook'. These proteins are known for their roles in changing the structure of DNA, which can switch genes on or off. This process might be how the cancer starts. Our latest findings suggest that when we block CBP and p300, we can stop the P3F protein from causing these harmful changes.
Armed with this knowledge, our project aims to dig deeper into the function of the 'hook' in P3F and its interaction with CBP and p300. Our first goal is to understand how this 'hook' drives the changes in DNA, leading to cancer. We will use advanced techniques to identify the other proteins that interact with the 'hook', and to measure the effects of disrupting the 'hook' on P3F's function. We will also study how it informs the 3D folding of DNA, an essential part of P3F's function.
Our second goal is to investigate the role of CBP and p300 in more detail. We have developed new molecular tools that can degrade these proteins, giving us a unique opportunity to understand their role in the cancer process. We aim to understand which of these proteins are essential for P3F to activate its target genes.
Through these studies, we hope to uncover the mechanisms through which P3F causes cancer. If successful, we could potentially develop drugs that target CBP and p300, effectively stopping P3F and preventing this type of cancer. This could provide a new therapeutic strategy for patients suffering from rhabdomyosarcoma.
