Structural studies of the ATRX-DAXX chromatin remodeller complex and its role in heterochromatin and telomere maintenance

Telomeres reside at the end of chromosomes that carry genetic information. Each time cells divide telomeres shorten until they become critically short and cells can no longer survive. Cancer cells upregulate the enzyme telomerase to prevent telomere shortening to achieve immortality. However, 10-15% of cancers do not use telomerase but instead rely on an alternative lengthening of telomere (ALT) pathway. Central to this are the proteins ATRX and DAXX which act together to deposit the regulatory protein, histone 3.3 (H3.3), into nucleosomes within our chromosome scaffold, particularly at telomeres to maintain its integrity. ATRX, DAXX and H3.3 have all been found to be mutated in cancers with ALT activation. I aim to visualise how ATRX and DAXX act together to deposit H3.3 into nucleosomes using the technique cryo-electron microscopy. This will provide mechanistic and functional insights into nucleosome regulation at telomeres by these important proteins in cancer pathogenesis.