Telomere protein TRF2 found on DNA fragments linked to inflammation after cells stop dividing
Telomere protein TRF2 found on DNA fragments linked to inflammation after cells stop dividing
On August 21, iScience published a study on senescent cells, which remain unable to divide for a prolonged period after damage. In several human cell models, the researchers found cytoplasmic DNA fragments carrying TRF2, a protein that protects telomeres at the ends of chromosomes. These fragments also carried markers of DNA damage and cGAS, a protein that detects DNA in the cytoplasm.
The nucleus keeps chromosomes contained within the cell. When DNA enters the cytoplasm, cGAS treats it as a danger signal and initiates an inflammatory response. In a senescent cell, this response sustains the SASP, a state in which the cell releases cytokines and other substances that alter its surrounding environment.
These experiments extend a 2017 study by Renuka Kandhaya-Pillai’s group. In that study, prolonged exposure to TNFα, an inflammatory signaling molecule, induced senescence in endothelial cells lining blood vessels and sustained cytokine release through STAT proteins. In the new study, the researchers asked which DNA might provide the cGAS signal in the same model.
They compared dividing cells with cells that had entered senescence because of repeated cell divisions or TNFα exposure. They also examined fibroblasts, which are connective tissue cells, from people with inherited premature aging syndromes or mutations in the LMNA gene. Across these models, TRF2 was detected on cytoplasmic fragments alongside γH2AX, a protein marker of DNA damage. Prolonged TNFα treatment reduced levels of lamin B1, a nuclear envelope protein. In microscopy images, the authors observed breaks in the nuclear envelope and the release of nuclear DNA into the cytoplasm.
A method that detects proteins located near one another showed that TRF2 and cGAS were in close proximity. In another experiment, TRF2 was found near active STAT1, a protein that activates some inflammatory response genes. In the TNFα model, ruxolitinib, which suppresses intracellular inflammatory signaling, reduced STAT1 and cGAS activity as well as the number of cytoplasmic fragments. In fibroblasts from patients with Werner syndrome, metformin and a JAK inhibitor reduced TRF2 foci, damage markers, and some components of the SASP. In TNFα-treated endothelial cells, metformin reduced only some of the measured markers.
In two mouse lines with chronically short telomeres, deletion of STING, a protein in the cGAS pathway, neither restored tissue function nor extended lifespan. The new study traces a narrower sequence of events in human cell models by linking disruption of the nuclear envelope to TRF2-positive fragments and inflammatory signaling.