Where's Telomerase?
Authors: Davenport R. John 
Published: August 2003

Location, location, location: the three most important words in real estate. New research suggests that position might also be crucial for telomerase, an enzyme that keeps chromosome ends from unraveling. The study reveals that the enzyme moves within the nucleus during the cell cycle and hints at a previously unknown way that cells control telomerase activity. The research also suggests that defects in the control mechanism might help cells turn cancerous.

Repeating DNA sequences called telomeres cap the ends of chromosomes and keep them from fraying like old shoelaces. But telomeres shrink every time a cell duplicates its DNA, and if the caps get too short, cells either stop dividing or die. To refurbish chromosome ends, cells use an enzyme called telomerase to tack on new telomere sequences. Telomerase isn't always a do-gooder: Many cancer cells carry defects that ramp up telomerase activity, enabling them to maintain long telomeres and divide indefinitely. Scientists knew that telomerase spends time in the nucleolus, a region of the nucleus where ribosomal RNA is produced. In the new work, Kathleen Collins, a cell biologist at the University of California, Berkeley, and colleagues investigated whether telomerase wanders elsewhere.

To follow telomerase, the researchers outfitted the protein with a visible beacon by connecting the gene that encodes one component of telomerase to a gene that produces a green fluorescent protein. Then they introduced the artificial DNA into fibroblasts--connective tissue cells--and looked for glowing telomerase at different stages of the cell cycle. They found that when cells hadn't started to replicate DNA, the nucleolus appeared green. But when cells were copying their DNA, nucleoli were darker and the rest of the nucleus instead appeared green. The enzyme gains access to the telomeres only when it exits the nucleolus, proposes Collins, because telomeres are thought to reside outside that region. Additional experiments showed that telomerase doesn't migrate in altered cells that can divide indefinitely. In these cells, the enzyme stained the whole nucleus during the entire cell cycle, and nucleoli were only dimly green. Always having telomerase in position might allow cells to stabilize broken chromosomes by adding telomeres to them; such breaks can result in genetic changes that turn cells cancerous, says Collins.

Further results suggest that by sequestering telomerase in the nucleolus most of the time, cells might prevent the enzyme from adding telomeres inappropriately. Collins's team irradiated tumor cells with gamma radiation, which breaks DNA. Untreated cells glowed green throughout the nucleus except for nucleoli. But after the damaging treatment, telomerase flocked to the nucleoli. Collins proposes that the shift prevents telomerase from gluing telomeres to the breaks before repair machinery can fix the them.

"It's a cool observation," says molecular biologist Christopher Counter of Duke University in Durham, North Carolina. The new work shows that cells might regulate the position of telomerase, "another level of control that we didn't know about." He cautions, however, that how telomerase's location influences the biology of a cell remains unclear. Future studies might reveal whether telomerase's value really depends on its neighborhood.

--R. John Davenport

J. M. Y. Wong, L. Kusdra, K. Collins, Subnuclear shuttling of human telomerase induced by transformation and DNA damage.
Nat. Cell Biol.
, 27 August 2002 [e-pub ahead of print].
[Abstract/Full Text]