title: Swi1Timeless Prevents Repeat Instability at Fission Yeast Telomeres.
abstract: Genomic instability associated with DNA replication stress is linked to cancer and genetic pathologies in humans. If not properly regulated, replication stress, such as fork stalling and collapse, can be induced at natural replication impediments present throughout the genome. The fork protection complex (FPC) is thought to play a critical role in stabilizing stalled replication forks at several known replication barriers including eukaryotic rDNA genes and the fission yeast mating-type locus. However, little is known about the role of the FPC at other natural impediments including telomeres. Telomeres are considered to be difficult to replicate due to the presence of repetitive GT-rich sequences and telomere-binding proteins. However, the regulatory mechanism that ensures telomere replication is not fully understood. Here, we report the role of the fission yeast Swi1(Timeless), a subunit of the FPC, in telomere replication. Loss of Swi1 causes telomere shortening in a telomerase-independent manner. Our epistasis analyses suggest that heterochromatin and telomere-binding proteins are not major impediments for telomere replication in the absence of Swi1. Instead, repetitive DNA sequences impair telomere integrity in swi1Δ mutant cells, leading to the loss of repeat DNA. In the absence of Swi1, telomere shortening is accompanied with an increased recruitment of Rad52 recombinase and more frequent amplification of telomere/subtelomeres, reminiscent of tumor cells that utilize the alternative lengthening of telomeres pathway (ALT) to maintain telomeres. These results suggest that Swi1 ensures telomere replication by suppressing recombination and repeat instability at telomeres. Our studies may also be relevant in understanding the potential role of Swi1(Timeless) in regulation of telomere stability in cancer cells.
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Mariana C
authors.initials: MC
authors.lastname: Gadaleta
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Mukund M
authors.initials: MM
authors.lastname: Das
authors.affiliation: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
authors.forename: Hideki
authors.initials: H
authors.lastname: Tanizawa
authors.affiliation: Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Ya-Ting
authors.initials: YT
authors.lastname: Chang
authors.affiliation: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Noma
authors.affiliation: Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Toru M
authors.initials: TM
authors.lastname: Nakamura
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Eishi
authors.initials: E
authors.lastname: Noguchi
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D042822:Genomic Instability; D006570:Heterochromatin / Q000235:genetics; D006801:Humans; D053842:Microsatellite Instability; D051721:Rad52 DNA Repair and Recombination Protein / Q000235:genetics; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*; D012568:Schizosaccharomyces / Q000235:genetics; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics*; D016615:Telomere / Q000235:genetics; D059505:Telomere Homeostasis; D059506:Telomere Shortening / Q000235:genetics; D034501:Telomere-Binding Proteins / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006570:Heterochromatin; C497194:RAD52 protein, human; D051721:Rad52 DNA Repair and Recombination Protein; D029702:Schizosaccharomyces pombe Proteins; D034501:Telomere-Binding Proteins; C513096:swi1 protein, S pombe