Understanding the function of ATRX in the alternative lengthening of telomeres (ALT) pathway

Part of what makes cancer cells so dangerous is their ability to divide, uncontrolled, forever. This requires them to prevent their telomeres (chromosome ends) from becoming too short, which would result in cell death. In ~15% of all cancers this is achieved via the alternative lengthening of telomeres (ALT) pathway. Moreover, these include particularly aggressive cancer types such as glioblastoma and pancreatic neuroendocrine tumours. The factor most commonly linked to ALT activity is mutation of the ATRX gene. However, loss of ATRX is not sufficient to induce ALT in human cells. We aim to study ALT and ATRX in a much simpler system, the nematode worm C. elegans. This simple animal model has been used with great success in academic research for decades. Our data shows that, in contrast to human cells, mutation of the worm ATRX homolog, xnp-1, is sufficient to activate ALT. Thus, worms provide an excellent system to directly study ATRX function, its involvement in ALT and the genetic vulnerabilities of ALT-positive cells. This will lay the groundwork for identifying potential new drug targets to inhibit ALT-positive cancers. As this project covers both in vivo and in vitro analyses, the student will receive training in a wide variety of skills including: molecular biology and cloning, genetics, ChIP and the generation and analysis of next generation DNA sequencing data.