Human telomerase RNA accumulation in Cajal bodies facilitates telomerase recruitment to telomeres and telomere elongation.
Telomerase is required for telomere maintenance and is responsible for the immortal phenotype of cancer cells. How telomerase is assembled and reaches telomeres in the context of nuclear architecture is not understood. Recently, the telomerase RNA subunit (hTR) was shown to accumulate in Cajal bodies (CBs), subnuclear structures implicated in ribonucleoprotein maturation. However, the functional relevance of this localization for telomerase was unknown. hTR localization to CBs requires a short sequence motif called the CAB box. Here, we reconstitute telomerase in human cells and determine the effects of CAB box mutations on telomere biology. We demonstrate that mutant hTR, which fails to accumulate in CBs, is fully capable of forming catalytically active telomerase in vivo but is strongly impaired in telomere extension. The functional deficiency is accompanied by a decreased association of telomerase with telomeres. Collectively, these data identify subnuclear localization as an important regulatory mechanism for telomere length homeostasis in human cells.
Cristofari
Gaël
G
Swiss Institute for Experimental Cancer Research, CH-1066 Epalinges, Switzerland.
Adolf
Emem
E
Reichenbach
Patrick
P
Sikora
Katarzyna
K
Terns
Rebecca M
RM
Terns
Michael P
MP
Lingner
Joachim
J
D002457:Cell Extracts; D020541:Coiled Bodies / Q000235:genetics* / Q000378:metabolism; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D009154:Mutation / Q000235:genetics; D009690:Nucleic Acid Conformation; D021381:Protein Transport; D012313:RNA / Q000737:chemistry / Q000378:metabolism*; D019098:Telomerase / Q000737:chemistry / Q000378:metabolism*; D016615:Telomere / Q000201:enzymology / Q000378:metabolism*
D002457:Cell Extracts; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase