Defect Transport Mechanism Leads to Shortened Chromosome Ends

Cell Division: Göttingen Scientists Decipher Biogenesis of Telomerase Enzyme Complex

Scientists at the University of Göttingen have deciphered the biogenesis of an enzyme complex whose role is to ensure that the ends of chromosomes are not shortened during the cell division process and that the genetic material is fully maintained. To be fully functional, telomerase RNA has to be shuttled in and out of the nucleus. If this process is disturbed, the enzyme complex is no longer able to do its job. The results were published in Cell Reports magazine.

Telomerase is an enzyme from the nucleus that consists of proteins and a non-coding RNA. The role of this enzyme complex is to lengthen the ends of the chromosomes (telomeres) after cell division in order to prevent a successive shortening of the genetic material (DNA) that automatically occurs when DNA is replicated. Whereas telomerase is not detectable in resting cells, it exists in growing tissue, i.e. in cells that are continuously dividing such as bone marrow cells, germline cells or embryonic stem cells as well as certain types of immune cells. It is also active in cancer cells, helping them to divide an infinite number of times and thus spread throughout the body. Unlike cancer cells, normal somatic cells undergo a finite number of cell divisions – they grow old and eventually die.

In their research at the Göttingen Center for Molecular Biosciences (GZMB) the scientists were now able to show how telomerase RNA is transported out of the nucleus into the ambient cytoplasm. There, outside the cell nucleus, it recruits proteins and matures into the large enzyme complex telomerase. Once functional, the telomerase is re-imported into the nucleus, where it attaches to the DNA and lengthens the ends of the chromosomes. "For the telomere elongation process to run smoothly, the RNA has to enter the cytoplasm and bind to the proteins it needs for the later process in the nucleus," says Professor Heike Krebber from the Molecular Genetics department at Göttingen University, who conducted the study together with her PhD students Haijia Wu and Daniel Becker. "Defects in this transport mechanism therefore lead to a successive shortening of the telomeres."

Further information: www.img.bio.uni-goettingen.de/Krebber-lab_homepage.html



Read full article:

Wu H, Becker D, and Krebber H:
Telomerase RNA TLC1 Shuttling to the Cytoplasm Requires mRNA Export Factors and Is Important for Telomere Maintenance

Cell Reports (2014), dx.doi.org/10.1016/j.celrep.2014.08.021


Telomerases protect the ends of linear chromosomes from shortening. They are composed of an RNA (TLC1 in S. cerevisiae) and several proteins. TLC1 undergoes several maturation steps before it is exported into the cytoplasm to recruit the Est proteins for complete assembly. The mature telomerase is subsequently reimported into the nucleus, where it fulfills its function on telomeres. Here, we show that TLC1 export into the cytoplasm requires not only the Ran GTPase-dependent karyopherin Crm1/Xpo1 but also the mRNA export machinery. mRNA export factor mutants accumulate mature and export-competent TLC1 RNAs in their nuclei. Moreover, TLC1 physically interacts with the mRNA transport factors Mex67 and Dbp5/Rat8. Most importantly, we show that the nuclear export of TLC1 is an essential step for the formation of the functional RNA containing enzyme, because blocking TLC1 export in the mex67-5 xpo1-1 double mutant prevents its cytoplasmic maturation and leads to telomere shortening.

Model for the life cycle of TLC1. TLC1 is generated in the nucleus by RNA polymerase II (RNAP II). Upon association of the Sm ring, the RNA is processed and the poly(A) tail removed by the nuclear exosome. The CAP is hypermethylated and a trimethylguanine (TMG) CAP is generated. The Ran-dependent nuclear export signal (NES) export receptor Crm1/Xpo1 associates via a currently unknown NES containing protein (X). Proper nuclear export additionally requires the mRNA export machinery; the export receptor heterodimer Mex67-Mtr2 associates and supports transport through the nuclear pore complex (NPC). Upon transit Mex67-Mtr2 is displaced by the DEAD box RNA helicase Dbp5 that is located at the cytoplasmic filaments of the NPC, where it interacts with Rat7/Nup159. The subsequent cytoplasmic maturation of the telomerase requires the association of several proteins including Est1, Est2, and Est3. The mature telomerase is reimported into the nucleus via the importins Mtr10 and Kap122, where it finally associates with the telomere ends.

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