Researchers identify new enzyme critical to maintaining human telomere length.


Telomeres are repetitive nucleotide sequences located at the termini of chromosomes.  Telomere shortening in humans can induce cellular old-age, which blocks cell division. This mechanism prevents genomic instability and development of cancer by limiting the number of cell divisions. However, shortened telomeres impair immune function that might also increase cancer susceptibility.  If telomeres become too short, the cell may detect this uncapping as DNA damage and then either stop growing, enter cellular old age, or begin programmed cell self-destruction depending on the cell’s genetic background. Many aging-related diseases are linked to shortened telomeres.

In mammalian germline cells and 85% of cancers, telomere length is maintained by the dimeric ribonucleoprotein telomerase.  Since the Nobel Prize-winning discovery of telomerase by the team in 1984, identifying other biological molecules that lengthen or shorten the protective caps on the ends of chromosomes has been slow going. Now, a study from researchers at Johns Hopkins has identified a previously unknown enzyme crucial to telomere length.  The group state that the new method they developed to find it should speed discovery of other proteins and processes that determine telomere length. The opensource study is published in the journal Cell Reports.

Previous studies show that in yeast, the preference of telomerase to extend the shortest telomeres requires the activity of Tel1, the yeast homolog of human ATM. ATM and ATR are kinases which regulate cellular responses to DNA damage, mRNA decay, and nutrient-dependent signaling. There is a large amount of evidence that their yeast homologs play a positive role in facilitating telomere extension by telomerase.  Figuring out exactly what’s needed to lengthen human telomeres has broad health implications as shortened telomeres have been implicated in aging and in diseases as diverse as lung and bone marrow disorders, while overly long telomeres are linked to cancer. Because telomeres naturally shorten each time DNA is copied in preparation for cell division, cells need a well-tuned process to keep adding the right number of building blocks back onto telomeres over an organism’s lifetime.  Research has been slowed due to a limiting and overtly long test for whether a given protein is involved in maintaining telomere length.

Earlier studies from the lab worked towards finding a better tool.  This started with a concept used for measuring telomere length in yeast. The hypothesis was to artificially cut mammalian cells’ telomeres, then detect elongation by telomerase, a test that would take less than a day, and could be performed even if the blocked proteins were needed for cells to divide. However, making the transition from yeast to mammals involved a host of unforeseen technical difficulties, and the project took nearly five years.  The current study used this new method to prove that both ATM and ATR are required for the recruitment of human telomerase to telomeres.

The current study used the new method, named Addition of De novo Initiated Telomeres (ADDIT) to examine the enzyme ATM kinase. The lab blocked the enzyme in lab-grown mouse cells, and used ADDIT to verify that it was indeed needed to lengthen telomeres. These data findings were validated using the old, three-month-long telomere test.

Results show that in normal mouse cells, a drug that blocks an enzyme called PARP1, activates ATM kinase to spur telomere lengthening. The group state that this finding offers proof-of-concept for drug-based telomere elongation to treat short-telomere diseases, such as bone marrow failure.  However, they go on to caution that PARP1 inhibitor drug itself doesn’t have the same telomere-elongating effect in human cells as it does in mouse cells.

The team surmise that ultimately ADDIT can help the global medical community understand how cells strike a balance between aging and the uncontrolled cell growth of cancer, which is very intriguing.  For the future, the researchers plan to use ADDIT to find out more about the telomere-lengthening biochemical pathway that ATM kinase is a part of, as well as other pathways that help determine telomere length.

Source: Johns Hopkins

 

The yeast homologs of the ATM and ATR DNA damage response kinases play key roles in telomerase-mediated telomere maintenance, but the role of ATM/ATR in the mammalian telomerase pathway has been less clear. Here, we demonstrate the requirement for ATM and ATR in the localization of telomerase to telomeres and telomere elongation in immortal human cells. Stalled replication forks increased telomerase recruitment in an ATR-dependent manner. Furthermore, increased telomerase recruitment was observed upon phosphorylation of the shelterin component TRF1 at an ATM/ATR target site (S367). This phosphorylation leads to loss of TRF1 from telomeres and may therefore increase replication fork stalling. ATM and ATR depletion reduced assembly of the telomerase complex, and ATM was required for telomere elongation in cells expressing POT1ΔOB, an allele of POT1 that disrupts telomere-length homeostasis. These data establish that human telomerase recruitment and telomere elongation are modulated by DNA-damage-transducing kinases.  ATM and ATR Signaling Regulate the Recruitment of Human Telomerase to Telomeres.  Bryan et al 2015.

The yeast homologs of the ATM and ATR DNA damage response kinases play key roles in telomerase-mediated telomere maintenance, but the role of ATM/ATR in the mammalian telomerase pathway has been less clear. Here, we demonstrate the requirement for ATM and ATR in the localization of telomerase to telomeres and telomere elongation in immortal human cells. Stalled replication forks increased telomerase recruitment in an ATR-dependent manner. Furthermore, increased telomerase recruitment was observed upon phosphorylation of the shelterin component TRF1 at an ATM/ATR target site (S367). This phosphorylation leads to loss of TRF1 from telomeres and may therefore increase replication fork stalling. ATM and ATR depletion reduced assembly of the telomerase complex, and ATM was required for telomere elongation in cells expressing POT1ΔOB, an allele of POT1 that disrupts telomere-length homeostasis. These data establish that human telomerase recruitment and telomere elongation are modulated by DNA-damage-transducing kinases. ATM and ATR Signaling Regulate the Recruitment of Human Telomerase to Telomeres. Bryan et al 2015.

One comment

  • This represents a significant step forward. This research and could signal the beginning of longevity possibilities hinted at by the discovery of Telomerase!

    Like

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