Understanding and Targeting the ALT Pathway in Human Breast Cancer

Telomeres, the protective elements at the ends of chromosomes, must be maintained for cells to proliferate indefinitely. In many human cancers, the telomeric DNA is replenished by the enzyme telomerase. However, a second pathway for telomere maintenance, referred to as the ALT pathway, has increasingly been recognized in human cancers. The genetic basis for activation of ALT is not known, but recent data have identified mutations and loss of ATRX protein as being hallmarks of ALTimmortalized cell lines and tumors. Our efforts to understand the mechanism by which loss of ATRX facilitates telomere recombination have uncovered a novel role for this protein in promoting telomere cohesion. Furthermore, disruption of telomere cohesion, in combination with telomere dysfunction, is capable of promoting the inappropriate non-sister telomere interactions that would facilitate the recombination-mediated mechanism of telomere maintenance in ALT cells. I have determined that ALT cells show evidence of telomere dysfunction, specifically telomere replication problems, and may also have disruptions to the Rif1BRCA1 pathways controlling homologous recombination repair. These defects, in combination with a telomere cohesion defect resulting from loss of ATRX, could facilitate the repair with non-sister telomeres that abolishes both template use and register, allowing the telomere recombination necessary for maintenance of ALT cells.