Abstract
Telomeres, the protective ends of eukaryotic chromosomes, are replicated through concerted actions of conventional DNA polymerases and elongated by telomerase, but the regulation of this process is not fully understood. Telomere replication requires (Ctc1/Cdc13)‐Stn1‐Ten1, a telomeric ssDNA‐binding complex homologous to RPA. Here, we show that the evolutionarily conserved phosphatase Ssu72 is responsible for terminating the cycle of telomere replication in fission yeast. Ssu72 controls the recruitment of Stn1 to telomeres by regulating Stn1 phosphorylation at Ser74, a residue located within its conserved OB‐fold domain. Consequently, ssu72∆ mutants are defective in telomere replication and exhibit long 3′‐ssDNA overhangs, indicative of defective lagging‐strand DNA synthesis. We also show that hSSU72 regulates telomerase activation in human cells by controlling recruitment of hSTN1 to telomeres. These results reveal a previously unknown yet conserved role for the phosphatase SSU72, whereby this enzyme controls telomere homeostasis by activating lagging‐strand DNA synthesis, thus terminating the cycle of telomere replication.
Highlights
Telomeres are protein-DNA complexes that form the ends of eukaryotic chromosomes
We performed cell cycle synchronization using a cdc25-22 block-release method in a ssu72-myc-tagged strain and measured Ssu72 binding to telomeres by chromatin immunoprecipitation (ChIP)
ChIP experiments consistently demonstrated an accumulation of Trt1myc at ssu72Δ telomeres compared to wt cells (Fig 1E)
Summary
Telomeres are protein-DNA complexes that form the ends of eukaryotic chromosomes (reviewed in Palm & de Lange, 2008). Due to G-rich repetitive DNA sequences and protective structures, telomeres represent a natural obstacle for passing replication forks (Maestroni et al, 2017), and replication fork collapse can lead to the loss of whole telomere tracts. To counteract these effects, telomerase (Trt in S. pombe and TERT in mammals) is responsible for adding specific repetitive sequences to telomeres, compensating for the cell’s inability to fully replicate chromosome ends (Greider & Blackburn, 1985). Specific telomere components are themselves required for proper telomere replication and telomere length regulation (Miller et al, 2006; Sfeir et al, 2009), suggesting that there is a thin line separating telomere replication and telomere elongation by telomerase
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