The fission yeast Stn1-Ten1 complex limits telomerase activity via its SUMO-interacting motif and promotes telomeres replication

Sci Adv. 2018 May 16;4(5):eaar2740. doi: 10.1126/sciadv.aar2740. eCollection 2018 May.

Abstract

Mammalian CST (CTC1-STN1-TEN1) complex fulfills numerous functions including rescue of the stalled replication forks and termination of telomerase action. In fission yeast lacking the CTC1 ortholog, the Stn1-Ten1 complex restricts telomerase action via its sumoylation-mediated interaction with Tpz1TPP1. We identify a small ubiquitin-like modifier (SUMO)-interacting motif (SIM) in the carboxyl-terminal part of Stn1 and show that this domain is crucial for SUMO and Tpz1-SUMO interactions. Point mutations in the SIM (Stn1-226) lead to telomere elongation, impair Stn1-Ten1 recruitment to telomeres, and enhance telomerase binding, revealing that Stn1 SIM domain contributes to the inhibition of telomerase activity at chromosome ends. Our results suggest that Stn1-Ten1 promotes DNA synthesis at telomeres to limit single-strand DNA accumulation. We further demonstrate that Stn1 functions in the replication of telomeric and subtelomeric regions in a Taz1-independent manner. Genetic analysis reveals that misregulation of origin firing and/or telomerase inhibition circumvents the replication defects of the stn1-226 mutant. Together, our results show that the Stn1-Ten1 complex has a dual function at telomeres by limiting telomerase action and promoting chromosome end replication.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Replication
  • DNA, Single-Stranded
  • Gene Expression
  • Models, Biological
  • Molecular Chaperones / chemistry
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Mutation
  • Protein Binding
  • Protein Interaction Domains and Motifs*
  • SUMO-1 Protein / chemistry
  • SUMO-1 Protein / metabolism
  • Schizosaccharomyces / physiology*
  • Schizosaccharomyces pombe Proteins / chemistry
  • Schizosaccharomyces pombe Proteins / genetics
  • Schizosaccharomyces pombe Proteins / metabolism*
  • Telomerase / metabolism*
  • Telomere / genetics*
  • Telomere / metabolism*
  • Telomere-Binding Proteins / chemistry
  • Telomere-Binding Proteins / genetics
  • Telomere-Binding Proteins / metabolism*

Substances

  • DNA, Single-Stranded
  • Molecular Chaperones
  • SUMO-1 Protein
  • Schizosaccharomyces pombe Proteins
  • Sti1 protein, S pombe
  • Telomere-Binding Proteins
  • Ten1 protein, S pombe
  • Telomerase