Recently published research out of the University of California, Berkeley provides a clearer view of the role telomere length and telomerase play in cell immortalization. That telomerase plays a part in immortalization has been known for decades; and scientists have long theorized that cancer cells become immortalized by turning on production of telomerase in cells that normally don't produce it, allowing these cells to keep their long telomeres indefinitely.
The UC Berkeley research, published today in Science, scrutinized the immortalization process using genome-engineered cells in culture and also tracked skin cells as they progressed from a mole into a malignant melanoma.
"Our findings have implications for how to think about the earliest processes that drive cancer and telomerase as a therapeutic target. It also means that the role of telomere biology at a very early step of cancer development is vastly underappreciated," said senior author Dirk Hockemeyer, a UC Berkeley assistant professor of molecular and cell biology.
Hockemeyer and his UC Berkeley team, in collaboration with dermatopathologist Boris Bastian and his colleagues at UCSF, found that immortalization is a two-step process, driven initially by a mutation that turns telomerase on, but at a very low level. That mutation is in the TERT promoter, a region upstream of the telomerase gene that regulates how much telomerase is produced.
The TERT promoter mutation does not generate enough telomerase to immortalize the pre-cancerous cells, but does delay normal cellular aging, Hockemeyer said, allowing more time for additional changes that turns telomerase up. He suspects that the telomerase levels are sufficient to lengthen the shortest telomeres, but not keep them all long and healthy.
If cells fail to turn up telomerase, they also fail to immortalize, and eventually die from short telomeres because chromosomes stick together and then shatter when the cell divides. Cells with the TERT promoter mutation are more likely to up-regulate telomerase, which allows them to continue to grow despite very short telomeres.
Yet, Hockemeyer says, telomerase levels are marginal, resulting is some unprotected chromosome ends in the surviving mutant cells, which could cause mutations and further fuel tumor formation.
"Before our paper, people could have assumed that the acquisition of just this one mutation in the TERT promoter was sufficient to immortalize a cell; that any time when that happens, the telomere shortening is taken out of the equation," Hockemeyer said. "We are showing that the TERT promoter mutation is not immediately sufficient to stop telomeres from shortening."
It is still unclear, however, what causes the eventual up-regulation of telomerase that immortalizes the cell. Hockemeyer says that it's unlikely to be another mutation, but rather an epigenetic change that affects expression of the telomerase gene, or a change in the expression of a transcription factor or other regulatory proteins that binds to the promoter upstream of the telomerase gene.