title: Dimerization of SLX4 contributes to functioning of the SLX4-nuclease complex.
abstract: The Fanconi anemia protein SLX4 assembles a genome and telomere maintenance toolkit, consisting of the nucleases SLX1, MUS81 and XPF. Although it is known that SLX4 acts as a scaffold for building this complex, the molecular basis underlying this function of SLX4 remains unclear. Here, we report that functioning of SLX4 is dependent on its dimerization via an oligomerization motif called the BTB domain. We solved the crystal structure of the SLX4BTB dimer, identifying key contacts (F681 and F708) that mediate dimerization. Disruption of BTB dimerization abrogates nuclear foci formation and telomeric localization of not only SLX4 but also of its associated nucleases. Furthermore, dimerization-deficient SLX4 mutants cause defective cellular response to DNA interstrand crosslinking agent and telomere maintenance, underscoring the contribution of BTB domain-mediated dimerization of SLX4 in genome and telomere maintenance.
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging/National Institutes of Health, 251 Bayview Blvd, Baltimore, MD 21044, USA.
authors.forename: Jinhu
authors.initials: J
authors.lastname: Yin
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 Shanghai Research Center, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Bingbing
authors.initials: B
authors.lastname: Wan
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging/National Institutes of Health, 251 Bayview Blvd, Baltimore, MD 21044, USA.
authors.forename: Jaya
authors.initials: J
authors.lastname: Sarkar
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging/National Institutes of Health, 251 Bayview Blvd, Baltimore, MD 21044, USA.
authors.forename: Kent
authors.initials: K
authors.lastname: Horvath
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.
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
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.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Shanghai Research Center, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Guangjuan
authors.initials: G
authors.lastname: Cheng
authors.affiliation: Shanghai Research Center, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Wan
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging/National Institutes of Health, 251 Bayview Blvd, Baltimore, MD 21044, USA.
authors.forename: Peiju
authors.initials: P
authors.lastname: Chin
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 Shanghai Research Center, Chinese Academy of Sciences, Shanghai 200031, China leim@sibcb.ac.cn.
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging/National Institutes of Health, 251 Bayview Blvd, Baltimore, MD 21044, USA liuyie@mail.nih.gov.
authors.forename: Yie
authors.initials: Y
authors.lastname: Liu
mesh_terms: D002460:Cell Line; D004720:Endonucleases / Q000378:metabolism*; D057927:Hydrophobic and Hydrophilic Interactions; D016685:Mitomycin / Q000633:toxicity; D000072417:Protein Domains; D055503:Protein Multimerization; D045522:Recombinases / Q000737:chemistry* / Q000378:metabolism; D016615:Telomere / Q000201:enzymology / Q000648:ultrastructure
chemical_list: D045522:Recombinases; D016685:Mitomycin; D004720:Endonucleases; C542319:SLX4 protein, human