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How telomeres protect cells from aging
The paper resulted from two telomere projects. In one, Diego Bonetti PhD, department of Biotecnology and Bioscience, University of Milano-Bicocca, Milano, Italy, looked into regulation of TERRA by the cell cycle and found TERRA levels change through its different stages. Arianna Lockhart and Marco Graf at Johannes Gutenberg, at the same time, were investigating the accumulation of TERRA on shortened telomeres. When they recognised TERRA accumulation differs between short and long telomeres, the two groups decided to join forces.
Quickly they realized TERRA accumulates on all telomeres. However, on long telomeres proteins Rat1 and RNase H2 rapidly remove TERRA. Yet the two proteins are not present on critically short telomeres. This suggested to them that TERRA is attached for a longer time to short telomeres perhaps to ensure repairs crucial to cell survival and continued divisions — before TERRA then falls off the longer, and now well functioning, telomere.
Although the work was carried out in yeast, telomeres and TERRA are found across all organisms with linear chromosomes. The research is expected to apply to humans as well. The teams will next look into human cell processes to verify any implications the presence of TERRA has on human cell ageing and cancer.
• Rif2 recruits RNase H2 and Rat1 specifically to long telomeres
• At long telomeres, TERRA and R-loops are degraded prior to telomere replication
• TERRA and R-loops accumulate as telomeres shorten which activates DDR
• TERRA R-loops promote homology-directed repair, avoiding premature senescence
Maintenance of a minimal telomere length is essential to prevent cellular senescence. When critically short telomeres arise in the absence of telomerase, they can be repaired by homology-directed repair (HDR) to prevent premature senescence onset. It is unclear why the specifically shortest telomeres are targeted for HDR. We demonstrate that non-coding RNA TERRA accumulates as HDR-promoting RNA-DNA hybrids (R-loops) preferentially at very short telomeres. The increased level of TERRA and R-loops, exclusively at short telomeres, is due to a local defect in RNA degradation by the Rat1 and RNase H2 nucleases, respectively. Consequently, the coordination of TERRA degradation with telomere replication is altered at shortened telomeres. R-loop persistence at short telomeres contributes to activation of the DNA damage response (DDR) and promotes recruitment of the Rad51 recombinase. Thus, the telomere length-dependent regulation of TERRA and TERRA R-loops is a critical determinant of the rate of replicative senescence.
Keywords: TERRA, R-loop, RNA-DNA hybrid, RNase H2, telomere, DDR, senescence, Rat1, Rif2
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TERRA accumulates on all telomeres. However, on long telomeres proteins Rat1
and RNase H2 rapidly remove TERRA. The two proteins are not present on critically
short telomeres. This suggests TERRA is attached to short telomeres in order to make
repairs crucial to cell survival and continued divisions — before falling off the telomere.
Image Credit: Brian Luke Lab, Johannes Gutenberg University