Human Stn1 protects telomere integrity by promoting efficient lagging-strand synthesis at telomeres and mediating C-strand fill-in

Abstract

Telomere maintenance is critical for genome stability. The newly-identified Ctc1/Stn1/Ten1 complex is important for telomere maintenance, though its precise role is unclear. We report here that depletion of hStn1 induces catastrophic telomere shortening, DNA damage response, and early senescence in human somatic cells. These phenotypes are likely due to the essential role of hStn1 in promoting efficient replication of lagging-strand telomeric DNA. Downregulation of hStn1 accumulates single-stranded G-rich DNA specifically at lagging-strand telomeres, increases telomere fragility, hinders telomere DNA synthesis, as well as delays and compromises telomeric C-strand synthesis. We further show that hStn1 deficiency leads to persistent and elevated association of DNA polymerase α (polα) to telomeres, suggesting that hStn1 may modulate the DNA synthesis activity of polα rather than controlling the loading of polα to telomeres. Additionally, our data suggest that hStn1 is unlikely to be part of the telomere capping complex. We propose that the hStn1 assists DNA polymerases to efficiently duplicate lagging-strand telomeres in order to achieve complete synthesis of telomeric DNA, therefore preventing rapid telomere loss.

Dynamic Interactions of Arabidopsis TEN1: Stabilizing Telomeres in Response to Heat Stress

“…"Activated" AtTEN1 has the potential to stabilize different conformations of CTC1 to coordinate several protein exchanges. For example, once the telomeric G-strand is extended by telomerase, CTC1/STN1 must swap telomerase for DNA Pol-a to enable synthesis of the C-rich telomeric strand (Huang et al, 2012;Qi and Zakian, 2000). In addition, when telomere replication is complete, Pol-a must be dislodged to generate a fully protected, inaccessible chromosome terminus.…”

MERISTEM DISORGANIZATION1Encodes TEN1, an Essential Telomere Protein That Modulates Telomerase Processivity inArabidopsis

“…As in yeast, vertebrate and plant CST interact with polymerase (pol) a (Casteel et al, 2009;Price et al, 2010;Huang et al, 2012;Nakaoka et al, 2012). Indeed, mammalian CTC1 and STN1 were first identified as pol a accessory factors (Casteel et al, 2009).…”

“…Indeed, mammalian CTC1 and STN1 were first identified as pol a accessory factors (Casteel et al, 2009). Biochemical studies reveal that vertebrate CST stimulates pol a/primase activity on telomeric substrates (Dai et al, 2010;Huang et al, 2012;Nakaoka et al, 2012) and promotes new origin firing at nontelomeric sites (Stewart et al, 2012). CST also interacts with the shelterin components TPP1 in human cells ) and POT1b in mice (Wu et al, 2012).…”

Human TEN1 Maintains Telomere Integrity and Functions in Genome-wide Replication Restart

“…Telomerase then extends the 3Ј overhang soon after duplex replication is complete (1). Finally, the complementary C-strand is filled in several hours later during late S/G 2 phase by polymerase ␣/primase (pol ␣) aided by CST (1,12,14,15).…”