title: 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.
authors.affiliation: School of Molecular Biosciences, WWAMI Medical Education Program, Washington State University, PO Box 1495, Spokane, WA 99210, USA.
authors.forename: Chenhui
authors.initials: C
authors.lastname: Huang
authors.forename: Xueyu
authors.initials: X
authors.lastname: Dai
authors.forename: Weihang
authors.initials: W
authors.lastname: Chai
mesh_terms: D002460:Cell Line; D016922:Cellular Senescence; D004256:DNA Polymerase I / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000378:metabolism; D015536:Down-Regulation; D016195:G2 Phase; D006367:HeLa Cells; D006801:Humans; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016196:S Phase; D016615:Telomere / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004277:DNA, Single-Stranded; D034741:RNA, Small Interfering; C544946:Stn1 protein, human; D034501:Telomere-Binding Proteins; D004256:DNA Polymerase I