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Telomere Length and Telomerase Activity; A Yin and Yang of Cell Senescence
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SMUG1 Promotes Telomere Maintenance through Telomerase RNA Processing.

Penelope Kroustallaki1, Lisa Lirussi1, Sergio Carracedo1

  • 1Department of Clinical Molecular Biology, University of Oslo, 0318 Oslo, Norway; Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, 1478 Lørenskog, Norway.

Cell Reports
|August 15, 2019
PubMed
Summary

Single-strand-selective uracil-DNA glycosylase (SMUG1) is crucial for telomerase biogenesis by processing telomeric RNA (hTERC). Its absence causes telomerase deficiency and impaired bone marrow proliferation.

Keywords:
RNA processingSMUG1TERCmodified basestelomere attrition

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Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Telomerase biogenesis is a complex, incompletely understood process.
  • The H/ACA ribonucleoprotein complex, containing DKC1, is vital for telomerase biogenesis.
  • Single-strand-selective uracil-DNA glycosylase (SMUG1) is known to associate with this complex.

Purpose of the Study:

  • To elucidate the role of SMUG1 in telomerase biogenesis.
  • To investigate SMUG1's interaction with telomeric RNA (hTERC) and its processing.
  • To understand the consequences of SMUG1 deficiency on telomerase function and cellular processes.

Main Methods:

  • Investigated SMUG1's interaction with hTERC.
  • Assessed the impact of SMUG1 on co-transcriptional processing of hTERC.
  • Analyzed base modifications in hTERC and their effect on DKC1 binding.
  • Studied RNA degradation pathways in SMUG1-deprived cells.
  • Examined telomerase activity and bone marrow proliferation in Smug1-knockout mice.

Main Results:

  • SMUG1 directly interacts with hTERC and is essential for its processing into mature form.
  • SMUG1 regulates base modifications in hTERC, influencing DKC1 binding.
  • Loss of SMUG1 leads to accumulation of aberrant hTERC intermediates and triggers their degradation via an EXOSC10-independent pathway.
  • SMUG1 deficiency results in telomerase deficiency and impaired bone marrow proliferation in knockout mice.

Conclusions:

  • SMUG1 plays a critical role in telomerase biogenesis by ensuring proper hTERC processing and modification.
  • Dysregulation of SMUG1 function leads to telomerase deficiency and associated cellular defects, impacting organismal health.