Lamping Jan-Philipp, Krebber Heike
Abteilung für Molekulare Genetik, Institut für Mikrobiologie und Genetik, Göttinger Zentrum für Molekulare Biowissenschaften (GZMB), Georg-August Universität Göttingen, 37077 Göttingen, Germany.
Nucleic Acids Res. 2025 Jun 6;53(11). doi: 10.1093/nar/gkaf480.
Telomere elongation is driven by telomerase, which consists of several proteins and the ncRNA component TLC1 in yeast. While many ncRNAs are terminated via the Nrd1-Nab3-Sen1 (NNS) pathway, we found that TLC1 requires cleavage and polyadenylation factor (CPF)-cleavage factor (CF) mediated 3'end processing and the resulting poly(A) tail to mature into a functional ribozyme. The poly(A) tail is predicted to fold back onto (U)-repeats potentially forming a terminal stem-loop structure that supports Sm-ring binding and thereby re-import into the nucleus after cytoplasmic shuttling. However, longer pre-TLC1 transcripts are predicted to fold differently, resulting in Sm-ring and import receptor binding defects, leaving them unable to overcome this cytoplasmic quality control checkpoint. To prevent cytoplasmic leakage of overlong transcripts, we propose an additional nuclear monitoring system, requiring Nrd1-Nab3 binding sites located between the first PAS motifs. CPF-CF formation might compete with Nrd1-Nab3 releasing them from shorter but not from longer transcripts facilitating their decay. This potential competitive RNA-binding of CPF-CF and Nrd1-Nab3 balances stability and decay.
端粒延长由端粒酶驱动，在酵母中端粒酶由几种蛋白质和非编码RNA组分TLC1组成。虽然许多非编码RNA通过Nrd1-Nab3-Sen1（NNS）途径终止，但我们发现TLC1需要切割和聚腺苷酸化因子（CPF）-切割因子（CF）介导的3'末端加工以及由此产生的聚（A）尾才能成熟为功能性核酶。聚（A）尾预计会回折到（U）重复序列上，可能形成一个末端茎环结构，该结构支持Sm环结合，从而在细胞质穿梭后重新导入细胞核。然而，预计较长的前TLC1转录本会有不同的折叠方式，导致Sm环和导入受体结合缺陷，使其无法克服这个细胞质质量控制检查点。为了防止超长转录本的细胞质泄漏，我们提出了一个额外的核监测系统，该系统需要位于第一个PAS基序之间的Nrd1-Nab3结合位点。CPF-CF的形成可能与Nrd1-Nab3竞争，将它们从较短的转录本中释放出来，但不会从较长的转录本中释放出来，从而促进它们的降解。CPF-CF和Nrd1-Nab3这种潜在的竞争性RNA结合平衡了稳定性和降解。
