title: SLX4 contributes to telomere preservation and regulated processing of telomeric joint molecule intermediates.
abstract: SLX4 assembles a toolkit of endonucleases SLX1, MUS81 and XPF, which is recruited to telomeres via direct interaction of SLX4 with TRF2. Telomeres present an inherent obstacle for DNA replication and repair due to their high propensity to form branched DNA intermediates. Here we provide novel insight into the mechanism and regulation of the SLX4 complex in telomere preservation. SLX4 associates with telomeres throughout the cell cycle, peaking in late S phase and under genotoxic stress. Disruption of SLX4's interaction with TRF2 or SLX1 and SLX1's nuclease activity independently causes telomere fragility, suggesting a requirement of the SLX4 complex for nucleolytic resolution of branched intermediates during telomere replication. Indeed, the SLX1-SLX4 complex processes a variety of telomeric joint molecules in vitro. The nucleolytic activity of SLX1-SLX4 is negatively regulated by telomeric DNA-binding proteins TRF1 and TRF2 and is suppressed by the RecQ helicase BLM in vitro. In vivo, in the presence of functional BLM, telomeric circle formation and telomere sister chromatid exchange, both arising out of nucleolytic processing of telomeric homologous recombination intermediates, are suppressed. We propose that the SLX4-toolkit is a telomere accessory complex that, in conjunction with other telomere maintenance proteins, ensures unhindered, but regulated telomere maintenance.
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging/National Institute of Health, 251 Bayview Blvd, Baltimore, MD 21224, USA.
authors.forename: Jaya
authors.initials: J
authors.lastname: Sarkar
authors.affiliation: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 333 Haike Road, Shanghai 200031, China Department of Biological Chemistry, University of Michigan Medical School, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, USA.
authors.forename: Bingbing
authors.initials: B
authors.lastname: Wan
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging/National Institute of Health, 251 Bayview Blvd, Baltimore, MD 21224, USA.
authors.forename: Jinhu
authors.initials: J
authors.lastname: Yin
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging/National Institute of Health, 251 Bayview Blvd, Baltimore, MD 21224, USA.
authors.forename: Haritha
authors.initials: H
authors.lastname: Vallabhaneni
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging/National Institute of Health, 251 Bayview Blvd, Baltimore, MD 21224, USA.
authors.forename: Kent
authors.initials: K
authors.lastname: Horvath
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging/National Institute of Health, 251 Bayview Blvd, Baltimore, MD 21224, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Kulikowicz
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging/National Institute of Health, 251 Bayview Blvd, Baltimore, MD 21224, USA.
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Yanbin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging/National Institute of Health, 251 Bayview Blvd, Baltimore, MD 21224, USA National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 333 Haike Road, Shanghai 200031, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging/National Institute of Health, 251 Bayview Blvd, Baltimore, MD 21224, USA liuyie@mail.nih.gov.
authors.forename: Yie
authors.initials: Y
authors.lastname: Liu
mesh_terms: D002453:Cell Cycle; D004247:DNA / Q000378:metabolism; D004706:Endodeoxyribonucleases; D004720:Endonucleases / Q000378:metabolism; D006367:HeLa Cells; D059765:Homologous Recombination; D006801:Humans; D053484:RecQ Helicases / Q000378:metabolism; D045522:Recombinases / Q000378:metabolism*; D012854:Sister Chromatid Exchange; D016615:Telomere / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000378:metabolism
chemical_list: D045522:Recombinases; D034501:Telomere-Binding Proteins; D004247:DNA; D004706:Endodeoxyribonucleases; D004720:Endonucleases; C542320:SLX1 protein, human; C542319:SLX4 protein, human; C097151:Bloom syndrome protein; D053484:RecQ Helicases