| Popis: |
A key requisite for indefinite growth of cancer cells is the ability to continuously elongate telomeres to circumvent the onset of senescence or apoptosis. In approximately 10 – 15% of cancers this is achieved through the Alternative Lengthening of Telomeres (ALT) pathway, a Break Induced Replication (BIR) mediated mechanism of telomere copying. ATRX has emerged as the key tumour suppressor in ALT cancers but its loss is insufficient to drive induction of the pathway. Here, we report that depletion of ATRX and/or DAXX in the presence of various genotoxic agents is sufficient to induce ALT. Moreover, co-deletion of ATRX and SETD2, commonly mutated in high grade gliomas (HGGs), elicits induction of ALT. Mechanistically, SETD2 restricts the accumulation of telomeric R-loops, which, in the absence of ATRX, leads to fork collapse and the loss of telomere sister chromatid cohesion. Cumulatively this provides a substrate for out of register BIR and telomere lengthening. |
