SMUG1 Promotes Telomere Maintenance through Telomerase RNA Processing

• Published in: Cell reports (Cambridge) Vol. 28; no. 7; pp. 1690 - 1702.e10
• Main Authors: Kroustallaki, Penelope, Lirussi, Lisa, Carracedo, Sergio, You, Panpan, Esbensen, Q. Ying, Götz, Alexandra, Jobert, Laure, Alsøe, Lene, Sætrom, Pål, Gagos, Sarantis, Nilsen, Hilde
• Format: Journal Article
• Language: English; Norwegian
• Published: United States Elsevier Inc 13.08.2019; Cell Press; Elsevier
• Subjects: modified bases; RNA processing; SMUG1; telomere attrition; TERC; SMUG1; modified bases; telomere attrition; RNA processing; TERC
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.07.040

Telomerase biogenesis is a complex process where several steps remain poorly understood. Single-strand-selective uracil-DNA glycosylase (SMUG1) associates with the DKC1-containing H/ACA ribonucleoprotein complex, which is essential for telomerase biogenesis. Herein, we show that SMUG1 interacts with the telomeric RNA component (hTERC) and is required for co-transcriptional processing of the nascent transcript into mature hTERC. We demonstrate that SMUG1 regulates the presence of base modifications in hTERC, in a region between the CR4/CR5 domain and the H box. Increased levels of hTERC base modifications are accompanied by reduced DKC1 binding. Loss of SMUG1 leads to an imbalance between mature hTERC and its processing intermediates, leading to the accumulation of 3′-polyadenylated and 3′-extended intermediates that are degraded in an EXOSC10-independent RNA degradation pathway. Consequently, SMUG1-deprived cells exhibit telomerase deficiency, leading to impaired bone marrow proliferation in Smug1-knockout mice. [Display omitted] •The SMUG1-DNA glycosylase promotes maturation of the telomeric DNA component, hTERC•SMUG1 regulates the presence of base modifications in hTERC•SMUG1 promotes DKC1 binding and stability of hTERC•hTERC levels limit telomerase activity in human SMUG1-knockout cells Kroustallaki et al. show that the single-strand-selective uracil-DNA glycosylase (SMUG1) functions in telomere maintenance, by removing modified bases from telomeric DNA and also by regulating modified bases in the telomerase RNA component (hTERC). SMUG1-knockout cells accumulate hTERC containing modified bases that interfere with binding of DKC1. Consequently, SMUG1-knockout cells and mice exhibit telomere maintenance defects.