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Balancing act at chromosome ends

Scientists identify novel regulator of telomere homeostasis

Cold Spring Harbor Laboratory

Each of our 46 chromosomes is capped by a telomere - a long stretch of repeated DNA (TTAGG). Telomeres play a key protective function in our cells, and now Dr. In Kwon Chung and colleagues at Yonsei University (Seoul, Korea) and the University of Central Florida reveal a novel mechanism to modulate telomere length.

Their work will be published in the April 1st issue of Genes & Development.

With each round of cell division, telomeres are progressively shortened. In fact, when telomeres reach a "critical length" the cell can no longer multiply. This has lead many scientists to conclude that the erosion of telomeres is a key feature of the aging process, while the aberrant addition to telomere ends (and increased proliferative capacity that this endows) is an integral part of cancer progression.

The mechanisms by which a cell regulates activity at its telomeres (be it positive or negative), is an actively investigated area, with direct implications for understanding aging and cancer.

Telomeres are elongated by an enzyme called Telomerase (hTERT). Telomerase is generally only active in fetal, germ, and cancer cells; it is normally repressed in most somatic (body) cells. This new work by Dr. Chung and colleagues shows how cells keep telomerase activity in check, by identifying a novel protein that tags its key partner for degradation.

Hsp90 is an abundant cellular protein that specifically interacts with hTERT to promote telomere formation. The Hsp90 protein is increased in several tumors and may increase the addition of telomere repeats several-fold. Chung's group has now identified a second protein, called MKRN1 that acts on hTERT to promote its degradation. MKRN1 belongs to a class of proteins called ubiquitin ligases that catalyze the addition of a small protein, called ubiquitin, to mark hTERT for destruction by cellular degradation machinery.

Increasing the amount of MKRN1 in cells promotes the degradation of hTERT and leads to a decreased telomerase activity. This degradation is even more pronounced in cells that are treated with the drug geldanamycin, which is a specific antagonist of Hsp90. Consequently, this causes the shortening of telomere lengths. Using biochemical assays, it was demonstrated that MKRN1 directly interacts with hTERT to promote the addition of the ubiquitin moieties.

These results indicate that two opposing forces in human cells influence basal levels of active hTERT. The first is an interaction with Hsp90 that promotes this activity and the other is protein degradation, mediated by MKRN1 and the balance of these two maintains cellular telomerase levels. The identification of MKRN1 as a negative regulator of telomere lengths is an important finding in elucidating how cells may achieve immortality to lead to cancers.

Further studies will be important to shed light on how MKRN1 may be used as a therapeutic target for checking the uncontrolled division of tumor cells. Dr. Chung is confident that "MKRN1 plays an important role in modulating telomere homeostasis through dynamic control of hTERT protein stability and could represent a novel target for anti-cancer drug development."

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