Like plastic tips, the ends of the laces protect and prevent them from shattering when tying them, called molecular tips as telomeres protect the ends of chromosomes and prevent them from melting when cells continually divide and duplicate their DNA. But while the loss of plastic tips can lead to messy cords, telomertab can lead to cancer.
Salk Institute researchers studying the relationship between telomeres and cancer made a surprising discovery: a cellular recovery process called autophagy – commonly thought of as a survival mechanism – actually promotes cell death, preventing cancer initiation.
The work, which appeared in the journal Nature on January 23, 2019, reveals autophagy to be a completely new tumor suppressant pathway and suggests that treatments to block the process in an attempt to reduce cancer may inadvertently promote it a lot. early.
"These results were a complete surprise," said Jan Karlseder, professor of Salk's Molecular and Cell Biology Laboratory and senior author of the magazine. "There are many control points that prevent cells from splitting out of control and becoming cancerous, but we didn't expect autophagy to be one of them."
Each time cells duplicate their DNA to share and grow, their telomeres get a little bit shorter. When telomeres become so short that they can no longer effectively protect chromosomes, the cells get a signal to stop sharing permanently. But sometimes, due to carcinogenic viruses or other factors, the cells do not receive the message and continue to divide. With dangerously short or missing telomeres, cells enter a condition called crisis, where the unprotected chromosomes can digest and become dysfunctional ̵
Karlseder's team wanted to better understand the crisis – both because crisis often results in widespread cell death that prevents precancerous cells from continuing to full blown cancer and since the mechanism underlying this beneficial cell death is not well understood.
"Many researchers believed that cell death in crisis occurs through apoptosis, which together with autophagy is one of two types of programmed cell death," said Joe Nassour, a postdoctoral researcher in the Karlseder Laboratory and the paper's first author. "But no one did experiments to find out if it really was the case."
To investigate the crisis and cell death that usually followed, Karlseder and Nassour used healthy human cells to drive a series of experiments where, in comparison, cells normally grow with cells as they are forced into crisis. By inactivating various growth-limiting genes (also known as tumor suppressor genes), their group enabled the cells to replicate with abandon, their telomeres become shorter and shorter during the process.
Knowing the type of cell death responsible for the major deaths in crisis examined the morphological and biochemical markers of both apoptosis and autophagy. Although both mechanisms were responsible for a small number of cells that die in the normally growing cells, autoscience was by far the dominant mechanism of cell death in the crisis group, where many more cells died.
The researchers then explored what happened when they prevented autophagy in the crisis cells. The results were striking: without cell death via autophagy to stop them replicating the cells tirelessly. Furthermore, when the team looked at the chromosomes of these cells, they were fused and disfigured, indicating that severe DNA damage by the species seen in cancer cells occurred and revealed autophagy to be an important early cancer suppression mechanism.
Finally, the team tested what happened when they induced specific types of DNA damage in normal cells, either to the ends of the chromosomes (via telomertab) or to middle regions. Cells with telomeric loss activated autophagy, while cells with DNA damage in other chromosomal regions activated apoptosis. This shows that apoptosis is not the only mechanism for destroying cells that can be precancerous due to DNA damage and that there is direct cross-talk between telomeres and autophagy.
The work reveals that rather than being a mechanism that burns unused growth of cancer cells (by cannibalizing other cells to recover raw materials), autophagy is actually a protection against such growth. Without autophagy, cells that lose other safety measures, such as tumor suppressive genes, progress to a crisis situation for uncontrolled growth, rampant DNA damage – and often cancer. (When cancer has started, autopage blocking may still be a valid strategy for starving a tumor, as a 2015 study by Salk Professor Reuben Shaw, a co-author of the current paper discovered.)
Karlseder, who holds Donald and Darlene Shiley Chair adds: "This work is exciting because it represents so many brand new discoveries. We didn't know it was possible for cells to survive the crisis; we didn't know that autophagy is involved in cell death in crisis; we certainly didn't know how autophagy prevents the accumulation of genetic damage. It opens up a whole new field of research that we are eager to continue. "
The next researcher plans to investigate closer the fragmentation in cell death pathways thereby causing damage to chromosome ends (telomeres) to autophagy while damaging others parts of chromosomes lead to apoptosis.