SMUG1 Promotes Telomere Maintenance through Telomerase RNA Processing

Abstract

Graphical Abstract Highlights d The SMUG1-DNA glycosylase promotes maturation of the telomeric DNA component, hTERC d SMUG1 regulates the presence of base modifications in hTERC d SMUG1 promotes DKC1 binding and stability of hTERC d hTERC levels limit telomerase activity in human SMUG1knockout cells

Telomere maintenance: regulating hTERC fate through RNA modifications

“…We, therefore, concluded that SMUG1 functions in rRNA quality control by regulating the presence of hmU. 4 In our recent study, 6 we showed that SMUG1 is required for maturation of hTERC in human cells by regulating the levels of modified bases located between the CR4-CR5 domain and the H-box, a region important for binding of Dyskerin pseudouridine synthase 1 (DKC1). In the absence of SMUG1, the balance between mature hTERC and its processing intermediates was disturbed.…”

“…In DNA, SMUG1 initiates Base Excision Repair (BER) of hmU, 5 but SMUG1 also has an RNA-processing function (Figure 1). 4,6 The recognition of RNA modifications by SMUG1 seemed to be coupled to RNA degradation: the accumulation of hmU in rRNA was accompanied by an increase in misprocessed rRNA species targeted for degradation and a reduction in the corresponding mature species. We, therefore, concluded that SMUG1 functions in rRNA quality control by regulating the presence of hmU.…”

“…hTERC levels could not be rescued after silencing of the main components of the RNA decay machinery, indicating that SMUG1 may play a role in targeting modified hTERC molecules to the exosome and/or to another yet-to-be-identified degradation pathway. 6 Some questions must be answered before we completely understand the role of SMUG1 in hTERC maturation. Firstly, the precise nature of the RNA modification recognized by SMUG1 in hTERC has not been identified.…”

“…However, we know it is a lesion specifically recognized and processed by SMUG1. 6 The most likely candidate is hmU because this modification accumulates in SMUG1depleted cells, and there is a possible biochemical route for its introduction. Secondly, we could not conclude as to whether the modification recognized by SMUG1 is a functional modification or damage.…”

“…This suggests that the modification might be a part of a regulated process aimed to fine-tune the levels of mature hTERC in human cells. 6 Targeting of SMUG1 to specific RNA species is likely mediated through direct interaction with DKC1 4 which, as part of an H/ACA ribonucleoprotein complex, contributes to the biogenesis and posttranscriptional processing of many types of RNA molecules, including hTERC. 7 Telomerase insufficiency in SMUG1-knockout cell led to dramatic telomere shortening.…”