Study Presents New Insights Into How Cancer Cells Overcome Telomere Shortening

A University of Oxford-led team has uncovered new details about how cancer cells overcome telomere shortening to allow themselves to divide indefinitely. The findings, which appear in Nucleic Acids Research this week, may lead to new cancer therapeutic approaches. Tumor cells use telomere maintenance mechanisms (TMMs) to enable unchecked proliferation and the majority of cancers achieve this through the upregulation of telomerase, a ribonucleoprotein that acts to progressively add telomeric repeats to the end of chromosomes. But new research has revealed that a subset of cancers maintain their telomere length through a telomerase-independent TMM called the alternative lengthening of telomeres (ALT) pathway. ALT cancers almost all feature the loss of the ATRX chromatin remodeler, but the other cellular events involved remain unknown. In this week's study, the scientists show that in ATRX-deficient cancer cells, increased trapping of proteins on DNA leads to replication fork stalling and collapse. At telomeres, this leads to ALT pathway activity, according to the study's authors. "Further insight into the basic biology of ALT cancer cells could lead to the design of more novel targeted chemotherapeutic agents and, eventually, to improved outcomes for individuals with [ALT-positive] cancers," they write.