Research in Developmental Cell shows that TIN2 preferentially binds to TRF1 and prevents Fbx4-mediated degradation.

Researchers have identified a cellular interaction that could hint at new approaches to blocking the cell-immortalizing effects of telomerase in cancer. The team, led by investigators at the University of Michigan Comprehensive Cancer Center, have found that a protein known as TIN2 overrides the trigger that allows telomerase to keep lengthening telomeres in cancer cells.

Their results are published in Developmental Cell in a paper titled “Structural Basis of Selective Ubiquitination of TRF1 by SCFFBx4.”  

The enzyme telomerase is a key player in the process that controls the lengths of telomeres at the ends of chromosomes, explain Ming Lei Ph.D., assistant professor of biological chemistry at the University of Michigan Medical School, and colleagues. In normal cells telomerase is kept in control by a protein known as TRF1. However, another protein, Fbx4, can bind to and degrade TRF1, giving telomerase free rein to continue lengthening the telomeres, essentially keeping them immortal.

The team has now identified a third protein called TIN2 that also interacts with TRF1 and appears to regulate the recognition of TRF1 by Fbx4. By binding to TRF1, TIN2 essentially prevents the Fbx4 interaction that leads to loss of telomerase control. Their research suggests that even in cases where both Fbx4 and TIN2 are present, TIN2 still dominates and binds to TRF1 first.

“In 90 percent of cancers, no matter what caused the cancer to form, it needs telomerase activity to maintain the cell,” Dr. Lei points out. “Without telomerase, the cell will die. Our work is key to understanding a detailed mechanism for how these molecules interact and how to design a drug to block Fbx4.” The researchers are now at the early stages of looking for peptides that mimic the ability of TIN2 to bind to TRF1.

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