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How telomeres protect cells from aging

Telomeres are molecular structures that exist at the "ends" of chromosomes. They have been compared to the plastic caps at the end of shoelaces which prevent the lace from unravelling.


However, the DNA ladder actually exists as a tightly bundled molecular knot within each cell nucleus. Only DNA stretched out during cell division appears ladder-like with telomeres as "end caps" at top and bottom. Until a cell divides, DNA is tightly wound within the cell nucleus, crammed inside that small permeable bubble. Energy races along the DNA knot with telomeres protecting the "ends" of the DNA tangle. That energy insures DNA is transcribed into new proteins keeping the cell dividing into new daughter cells.

Over time, however, telomeres wear down and gradually shorten with each cell division and their protective ability becomes less and less effective. Slowing down translates into a slowdown in protein production as well. The intricate cycle of energy transferance and protein production becomes out of balance and cells stop dividing and die. If the balance of energy transfer shifts too much out of balance in another direction, cells divide too frequently and cancer ensues. Over all, the process of self-correction with proteins needed for repair stops.

When telomeres become too short, a signal is released telling the cell to stop dividing as the genetic material is compromised. Shortened telomeres and reduced numbers of cell divisions are hallmarks of ageing. However, telomere shortening can also act as a defense against cancer as highly proliferative cells only divide when telomeres are not shortened. So, telomere length is a double-edged sword. It must be carefully regulated to strike a balance between ageing and cancer prevention.
"In the life of a cell, you have to find some sort of balance between cancer prevention and ageing. Telomeres are at the nexus between the two, so understanding how they are maintained is really important."

Brian Luke PhD, Professor, Developmental Biology and Neurobiology, and Adjunct Director of the Institute of Molecular Biology (IMB), Johannes Gutenberg (JGU) Institute, Mainz, Germany.

Luke is interested in understanding how a cell recognizes shortened and damaged telomeres without caps. His group also wanted to identify those factors promoting repair of short telomeres. All of this information helps scientists understand why cells either become senescent or continue growing, even if over growing as in the case of cancer.

In their recent paper, published in the journal Cell, Luke and his team show that one of the keys to understanding how damaged telomeres do or do not repair, is TERRA, a species of RNA that accumulates specifically at the ends of critically short telomeres. TERRA binds directly to DNA signalling that cell this telomere should be repaired, so that it can continue dividing and making daughter cells.
"We already knew that short telomeres play a key role in determining the onset of cellular senescence, but we didn't really understand which features of short telomeres were important. What we have found with TERRA is an intricate regulatory system that explains how short telomeres are identified by the cell."

Brian Luke PhD

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.

Highlights
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

Summary
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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Jul 21, 2017   Fetal Timeline   Maternal Timeline   News   News Archive




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



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