title: The Werner Syndrome Helicase Coordinates Sequential Strand Displacement and FEN1-Mediated Flap Cleavage during Polymerase δ Elongation.
abstract: The Werner syndrome protein (WRN) suppresses the loss of telomeres replicated by lagging-strand synthesis by a yet to be defined mechanism. Here, we show that whereas either WRN or the Bloom syndrome helicase (BLM) stimulates DNA polymerase δ progression across telomeric G-rich repeats, only WRN promotes sequential strand displacement synthesis and FEN1 cleavage, a critical step in Okazaki fragment maturation, at these sequences. Helicase activity, as well as the conserved winged-helix (WH) motif and the helicase and RNase D C-terminal (HRDC) domain play important but distinct roles in this process. Remarkably, WRN also influences the formation of FEN1 cleavage products during strand displacement on a nontelomeric substrate, suggesting that WRN recruitment and cooperative interaction with FEN1 during lagging-strand synthesis may serve to regulate sequential strand displacement and flap cleavage at other genomic sites. These findings define a biochemical context for the physiological role of WRN in maintaining genetic stability.
authors.affiliation: Department of Molecular Microbiology and Immunology, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Baomin
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Medicine, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Sita
authors.initials: S
authors.lastname: Reddy
authors.affiliation: Department of Molecular Microbiology and Immunology, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA comai@med.usc.edu.|Department of Biochemistry and Molecular Medicine, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Lucio
authors.identifier: http://orcid.org/0000-0003-3109-1841
authors.initials: L
authors.lastname: Comai
mesh_terms: D020816:Amino Acid Motifs; D004247:DNA / Q000096:biosynthesis; D004258:DNA Polymerase III / Q000378:metabolism*; D004261:DNA Replication; D045585:Flap Endonucleases / Q000378:metabolism*; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D058105:Polymerization; D000072417:Protein Domains; D053484:RecQ Helicases / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D013379:Substrate Specificity; D016615:Telomere / Q000378:metabolism; D000071657:Werner Syndrome Helicase / Q000737:chemistry / Q000378:metabolism*
chemical_list: D004247:DNA; D004258:DNA Polymerase III; D045585:Flap Endonucleases; C468317:FEN1 protein, human; C097151:Bloom syndrome protein; D053484:RecQ Helicases; D000071657:Werner Syndrome Helicase
keywords: DNA helicase; DNA replication; Okazaki fragment; Werner syndrome; aging; lagging strand; lagging-strand synthesis; telomeres