September 20, 2022 -- Increasing levels of telomeric repeat-containing RNA (TERRA) damages the DNA of cancers with a particular form of replicative immortality and leads to cell death, according to Portuguese researchers who show that “anti-aging clocks” can be used to kill cancer cells.
Their study, published September 19 in Proceedings of the National Academy of Sciences, focuses on alternative lengthening of telomeres (ALT) cancers. Telomeres are proteins at the ends of chromosomes that function as a cell aging clock. While most cancers use an enzyme called telomerase to counteract the shortening of chromosome ends, ALT cancers -- which account for around 10% of human tumors -- reelongate telomeres to achieve immortality. ALT cancers are more resistant to chemotherapy.
In an earlier paper in the journal Nature Communications, researchers at Portugal's Instituto de Medicina Molecular showed that inhibiting TERRA, a class of long noncoding RNAs transcribed at telomeres, suppresses telomere damage and ALT features. After showing that inhibiting TERRA transcription alleviates ALT activity, the researchers questioned what happens when excessive ALT is triggered.
Their latest study is an attempt to answer that question. In the paper, the researchers expand on their earlier findings by showing TERRA transcription causes rapid loss of telomeric DNA through a pathway that requires an endonuclease.
"When the levels of TERRA are increased, the damage at telomeres also increases and this becomes so heavy that even a cancer cell that usually is more resistant, is not able to multiply anymore," Bruno Silva, PhD, first author of the study, said in a statement. "The consequence for the cancer cell is catastrophic. The cell cannot take multiple damaged telomeres and stops dividing."
TERRA is only found at very low levels in healthy cells and its physiological function is largely unknown. The molecules are more abundant in ALT cancer cells. When the researchers further increased TERRA levels inside the ALT cancer cells, they saw the accumulation of damage in the DNA of the telomeres.
In response, ALT cancer cells activate maintenance of the damaged telomere and use up other telomeres trying to restore the damage. The presence of multiple damaged telomeres causes the cancer cells to stop dividing. Coupled to the previous paper, the latest research suggests that increasing or decreasing TERRA transcription should hinder cancer cell proliferation by compromising telomere maintenance, offering the potential to develop therapeutic protocols for treatment of ALT cancers based on the manipulation of TERRA production.
"This makes TERRA a uniquely versatile target for therapy," Claus Azzalin, PhD, one of the authors of the paper, said. "By decreasing its levels, we can block telomere maintenance, as we have shown before, while by increasing TERRA levels, we can rise the damage to levels that are not sustainable even for a cancer cell, eventually leading to cell death."