Abteilung für Molekulare Genetik, Institut für Mikrobiologie Und Genetik, Göttinger Zentrum für Molekulare Biowissenschaften (GZMB), Georg-August Universität Göttingen, Göttingen, Germany.
Philipps-Universität Marburg, Klinik für Dermatologie Und Allergologie, Baldingerstraße, 35043, Marburg, Germany.
Sci Rep. 2021 Nov 12;11(1):22174. doi: 10.1038/s41598-021-01599-3.
Telomerases elongate the ends of chromosomes required for cell immortality through their reverse transcriptase activity. By using the model organism Saccharomyces cerevisiae we defined the order in which the holoenzyme matures. First, a longer precursor of the telomerase RNA, TLC1 is transcribed and exported into the cytoplasm, where it associates with the protecting Sm-ring, the Est and the Pop proteins. This partly matured telomerase is re-imported into the nucleus via Mtr10 and a novel TLC1-import factor, the karyopherin Cse1. Remarkably, while mutations in all known transport factors result in short telomere ends, mutation in CSE1 leads to the amplification of Y' elements in the terminal chromosome regions and thus elongated telomere ends. Cse1 does not only support TLC1 import, but also the Sm-ring stabilization on the RNA enableling Mtr10 contact and nuclear import. Thus, Sm-ring formation and import factor contact resembles a quality control step in the maturation process of the telomerase. The re-imported immature TLC1 is finally trimmed into the 1158 nucleotides long mature form via the nuclear exosome. TMG-capping of TLC1 finalizes maturation, leading to mature telomerase.
端粒酶通过其逆转录酶活性延长细胞永生所需的染色体末端。通过使用模式生物酿酒酵母，我们定义了全酶成熟的顺序。首先，较长的端粒酶 RNA 前体 TLC1 被转录并输出到细胞质中，在那里它与保护 Sm 环、Est 和 Pop 蛋白结合。这种部分成熟的端粒酶通过 Mtr10 和一种新的 TLC1 导入因子核孔蛋白 Cse1 重新导入细胞核。值得注意的是，虽然所有已知的运输因子的突变都会导致端粒变短，但 CSE1 的突变会导致末端染色体区域的 Y' 元件扩增，从而导致端粒延长。Cse1 不仅支持 TLC1 的导入，还能稳定 RNA 上的 Sm 环，使 Mtr10 接触并进行核导入。因此，Sm 环的形成和导入因子的接触类似于端粒酶成熟过程中的质量控制步骤。重新导入的不成熟的 TLC1 最终通过核 exosome 修剪成 1158 个核苷酸长的成熟形式。TLC1 的 TMG 加帽完成成熟，导致成熟的端粒酶。
