SMUG1 Promotes Telomere Maintenance through Telomerase RNA Processing
Penelope Kroustallaki,
Lisa Lirussi,
Sergio Carracedo,
Panpan You,
Q. Ying Esbensen,
Alexandra Götz,
Laure Jobert,
Lene Alsøe,
Pål Sætrom,
Sarantis Gagos,
Hilde Nilsen
Affiliations
Penelope Kroustallaki
Department of Clinical Molecular Biology, University of Oslo, 0318 Oslo, Norway; Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, 1478 Lørenskog, Norway
Lisa Lirussi
Department of Clinical Molecular Biology, University of Oslo, 0318 Oslo, Norway; Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, 1478 Lørenskog, Norway
Sergio Carracedo
Department of Clinical Molecular Biology, University of Oslo, 0318 Oslo, Norway; Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, 1478 Lørenskog, Norway
Panpan You
Department of Clinical Molecular Biology, University of Oslo, 0318 Oslo, Norway; Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, 1478 Lørenskog, Norway
Q. Ying Esbensen
Department of Clinical Molecular Biology, University of Oslo, 0318 Oslo, Norway; Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, 1478 Lørenskog, Norway
Alexandra Götz
Department of Clinical Molecular Biology, University of Oslo, 0318 Oslo, Norway; Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, 1478 Lørenskog, Norway
Laure Jobert
Department of Clinical Molecular Biology, University of Oslo, 0318 Oslo, Norway
Lene Alsøe
Department of Clinical Molecular Biology, University of Oslo, 0318 Oslo, Norway; Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, 1478 Lørenskog, Norway
Pål Sætrom
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, 7491 Trondheim, Norway; Department of Computer Science, Norwegian University of Science and Technology, NTNU, 7491 Trondheim, Norway; Bioinformatics Core Facility-BioCore, Norwegian University of Science and Technology, NTNU, 7491 Trondheim, Norway; K.G. Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology, NTNU, 7491 Trondheim, Norway
Sarantis Gagos
Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation, Academy of Athens, Athens, Greece
Hilde Nilsen
Department of Clinical Molecular Biology, University of Oslo, 0318 Oslo, Norway; Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, 1478 Lørenskog, Norway; Corresponding author
Summary: 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. : 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. Keywords: SMUG1, telomere attrition, TERC, modified bases, RNA processing
