Discovery could throw new light on ALT mechanism by which some tumor cells rebuild their telomeres.
Scientists have discovered that the ends of telomeres in some human cancer cells carry a cytosine-rich (C-rich) overhang that has only ever previously been identified in the nematode Caenorhabditis elegan. They claim the discovery could shed new light on the homologous recombination-based mechanism of telomere rebuilding that is used by about 10% of cancer cells to retain their immortality.
Liana Oganesian Ph.D., and Jan Karlseder, Ph.D., at the Salk Institute for Biological Studies’ molecular and cellular biology laboratory, report their findings in Molecular Cell. The paper is titled “Mammalian 5’ C-Rich Telomeric Overhangs Are a Mark of Recombination-Dependent Telomere Maintenance strategy.”
The G overhang in human chromosomes is vital for the mechanism by which the vast majority of cancer cells use telomerase to maintain telomere length and thus retain the ability to keep dividing. However, about 10% of cancer cells use a different, homologous recombination technique for building up telomeres known as alternative lengthening of telomeres, or ALT.
Drs. Oganesian and Karlseder previously identified a cytosine-rich counterpart at the 5’ ends of chromosomes in C. elegans. In this animal the G- and C-rich telomeric tails are equally abundant, but when a protein which the C-tails interact with was removed from cells, the worms begin to exhibit characteristics evident in human ALT tumors. It was these findings that prompted the researchers to re-examine the end structure of mammalian telomeres.
Surprisingly, they found the same 5’C-rich overhang at the ends of telomeres in about half of human tumor cells engaged in the ALT pathway of telomere maintenance as well as in mouse embryonic fibroblasts. The C-rich overhang was prevalent at all phases of the cell cycle and, importantly, they stress, persisted in arrested cells, “indicating that it is unlikely to be an artefact of DNA replication.” Moreover, telomeric C-overhanging levels in human ALT cells were greatly perturbed when three key proteins (RAD51, RAD52, and XRCC3) involved in homologous recombination were knocked out using siRNAs.
“Based on these findings we propose that the C-rich overhang is an outcome and driver of HR-dependent telomere maintenance,” the authors conclude. “The occurrence of C overhangs may be linked with the pathway of recombination that is dependent on rolling-circle amplification. While it remains uncertain whether such a pathway is active at mammalian telomeres, characterization of the 5’ overhang may provide insight in better understanding of telomerase-independent telomere maintenance.”