Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Institute of Developmental Biology and Neurobiology, Johannes Gutenberg University, Mainz, Germany.
Nat Commun. 2024 Jul 15;15(1):5955. doi: 10.1038/s41467-024-50422-w.
Human telomerase assembly is a highly dynamic process. Using biochemical approaches, we find that LARP3 and LARP7/MePCE are involved in the early stage of human telomerase RNA (hTR) and that their binding to RNA is destabilized when the mature form is produced. LARP3 plays a negative role in preventing the processing of the 3'-extended long (exL) form and the binding of LARP7 and MePCE. Interestingly, the tertiary structure of the exL form prevents LARP3 binding and facilitates hTR biogenesis. Furthermore, low levels of LARP3 promote hTR maturation, increase telomerase activity, and elongate telomeres. LARP7 and MePCE depletion inhibits the conversion of the 3'-extended short (exS) form into mature hTR and the cytoplasmic accumulation of hTR, resulting in telomere shortening. Taken together our data suggest that LARP3 and LARP7/MePCE mediate the processing of hTR precursors and regulate the production of functional telomerase.
人类端粒酶组装是一个高度动态的过程。通过生化方法，我们发现 LARP3 和 LARP7/MePCE 参与人类端粒酶 RNA（hTR）的早期阶段，当产生成熟形式时，它们与 RNA 的结合被破坏。LARP3 在防止 3'-延伸长（exL）形式的加工和 LARP7 和 MePCE 的结合方面起着负作用。有趣的是，exL 形式的三级结构阻止了 LARP3 的结合并促进了 hTR 的生物发生。此外，LARP3 的低水平促进 hTR 的成熟，增加端粒酶活性，并延长端粒。LARP7 和 MePCE 的耗竭抑制了 3'-延伸短（exS）形式向成熟 hTR 的转化和 hTR 的细胞质积累，导致端粒缩短。总之，我们的数据表明 LARP3 和 LARP7/MePCE 介导 hTR 前体的加工，并调节功能性端粒酶的产生。
