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

Cancers upregulate telomerase in order to lengthen telomeres and therby to propagate their survival and immortality.

However, in 10-15% of cancers, telomere length is instead maintained by the alternative lengthening of telomere (ALT) pathway.

A breakthrough in understanding this pathway came when ATRX (alpha thalassemia/mental retardation X-linked), a chromatin remodeller with various regulatory roles throughout the genome, was discovered to be mutated or lost in ~90% of ALT cancer cell lines and tumours.

An important mechanism of ATRX function is in conjunction with DAXX, the histone 3.3 (H3.3) chaperone, whose mutations are also associated with ALT activation.

ATRX and DAXX act together to deposit H3.3 and its binding partner H4 at heterochromatin, such as telomeres, aided by HP1.

Deposition of H3.3 helps to maintain telomeres in a canonical state, preventing aberrent secondary DNA structure formation leading to activation of the ALT pathway. My proposal is to elucidate, by cryo-EM, the structure of HP1-ATRX-DAXX-H3.3-H4 in complex with the nucleosome.

This structure would provide functional and mechanistic insights into chromatin remodelling, and histone deposition by this central ALT associated complex. This field is clinically exciting, as targeting the ALT pathway is a promising therapeutic approach for cancer.