title: Human CST promotes telomere duplex replication and general replication restart after fork stalling.
abstract: Mammalian CST (CTC1-STN1-TEN1) associates with telomeres and depletion of CTC1 or STN1 causes telomere defects. However, the function of mammalian CST remains poorly understood. We show here that depletion of CST subunits leads to both telomeric and non-telomeric phenotypes associated with DNA replication defects. Stable knockdown of CTC1 or STN1 increases the incidence of anaphase bridges and multi-telomeric signals, indicating genomic and telomeric instability. STN1 knockdown also delays replication through the telomere indicating a role in replication fork passage through this natural barrier. Furthermore, we find that STN1 plays a novel role in genome-wide replication restart after hydroxyurea (HU)-induced replication fork stalling. STN1 depletion leads to reduced EdU incorporation after HU release. However, most forks rapidly resume replication, indicating replisome integrity is largely intact and STN1 depletion has little effect on fork restart. Instead, STN1 depletion leads to a decrease in new origin firing. Our findings suggest that CST rescues stalled replication forks during conditions of replication stress, such as those found at natural replication barriers, likely by facilitating dormant origin firing.
authors.affiliation: Department of Cancer and Cell Biology, University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Stewart
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Mary F
authors.initials: MF
authors.lastname: Chaiken
authors.forename: Christopher
authors.initials: C
authors.lastname: Kasbek
authors.forename: Paul D
authors.initials: PD
authors.lastname: Chastain
authors.forename: Woodring E
authors.initials: WE
authors.lastname: Wright
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Price
mesh_terms: D045744:Cell Line, Tumor; D004261:DNA Replication; D055785:Gene Knockdown Techniques; D042822:Genomic Instability; D006801:Humans; D016615:Telomere / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000235:genetics*; D035321:Telomeric Repeat Binding Protein 1 / Q000235:genetics
chemical_list: C544945:Ctc1 protein, human; C544946:Stn1 protein, human; D034501:Telomere-Binding Proteins; D035321:Telomeric Repeat Binding Protein 1