SMUG1 promotes telomere maintenance through telomerase RNA end-processing

Single-strand selective uracil DNA-glycosylase (SMUG1) associates with the DKC1-H/ACA ribonucleoprotein complex, which is essential for telomerase biogenesis. We show herein, that SMUG1 interacts with the telomerase RNA component, hTERC, and is required for co-transcriptional processing of the nascent transcript towards mature hTERC. We demonstrate that SMUG1 regulates the presence of base modifications between the CR4/CR5 region and the H-box situated towards the 3´-end of hTERC. 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, present telomerase deficiency leading to impaired bone marrow proliferation in SMUG1-knockout mice. Analysis of differential expressed genes in HAP1 SMUG1 WT and SMUG1 KO cells generated by deep sequencing (in triplicate).