SLX4

Summary

Gene Symbol: SLX4
Description: SLX4 structure-specific endonuclease subunit
Alias: BTBD12, FANCP, MUS312, structure-specific endonuclease subunit SLX4, BTB/POZ domain-containing protein 12
Species: human
Products:     SLX4

Top Publications

  1. Garner E, Kim Y, Lach F, Kottemann M, Smogorzewska A. Human GEN1 and the SLX4-associated nucleases MUS81 and SLX1 are essential for the resolution of replication-induced Holliday junctions. Cell Rep. 2013;5:207-15 pubmed publisher
    ..In vitro, HJs may be nucleolytically processed by MUS81-EME1, GEN1, and SLX4-SLX1. Here, we exploit human SLX4-null cells to examine the requirements for HJ resolution in vivo...
  2. Yamamoto K, Kobayashi S, Tsuda M, Kurumizaka H, Takata M, Kono K, et al. Involvement of SLX4 in interstrand cross-link repair is regulated by the Fanconi anemia pathway. Proc Natl Acad Sci U S A. 2011;108:6492-6 pubmed publisher
    ..However, ICL processing has been shown to also involve MUS81-EME1 and XPF-ERCC1, nucleases known to interact with SLX4, a docking protein that also can bind another nuclease, SLX1...
  3. Landwehr R, Bogdanova N, Antonenkova N, Meyer A, Bremer M, Park Simon T, et al. Mutation analysis of the SLX4/FANCP gene in hereditary breast cancer. Breast Cancer Res Treat. 2011;130:1021-8 pubmed publisher
    b>SLX4 coordinates three structure-specific endonucleases in the DNA damage response. One subtype of Fanconi anaemia, FA-P, has recently been attributed to biallelic SLX4 gene mutations...
  4. Wyatt H, Sarbajna S, Matos J, West S. Coordinated actions of SLX1-SLX4 and MUS81-EME1 for Holliday junction resolution in human cells. Mol Cell. 2013;52:234-47 pubmed publisher
    ..Here, we show that three structure-selective endonucleases, namely SLX1-SLX4, MUS81-EME1, and GEN1, define two pathways of HJ resolution in human cells...
  5. Kim Y, Lach F, Desetty R, Hanenberg H, Auerbach A, Smogorzewska A. Mutations of the SLX4 gene in Fanconi anemia. Nat Genet. 2011;43:142-6 pubmed publisher
    ..anemia and show that the cellular defects in these individuals' cells are complemented by wildtype SLX4, demonstrating that biallelic mutations in SLX4 (renamed here as FANCP) cause a new subtype of Fanconi anemia, Fanconi anemia-P.
  6. Stoepker C, Hain K, Schuster B, Hilhorst Hofstee Y, Rooimans M, Steltenpool J, et al. SLX4, a coordinator of structure-specific endonucleases, is mutated in a new Fanconi anemia subtype. Nat Genet. 2011;43:138-41 pubmed publisher
    ..b>SLX4, which coordinates three separate endonucleases, was recently recognized as an important regulator of DNA repair...
  7. Bogliolo M, Schuster B, Stoepker C, Derkunt B, Su Y, Raams A, et al. Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia. Am J Hum Genet. 2013;92:800-6 pubmed publisher
  8. Kim Y, Spitz G, Veturi U, Lach F, Auerbach A, Smogorzewska A. Regulation of multiple DNA repair pathways by the Fanconi anemia protein SLX4. Blood. 2013;121:54-63 pubmed publisher
    SLX4, the newly identified Fanconi anemia protein, FANCP, is implicated in repairing DNA damage induced by DNA interstrand cross-linking (ICL) agents, topoisomerase I (TOP1) inhibitors, and in Holliday junction resolution...
  9. Andersen S, Bergstralh D, Kohl K, Larocque J, Moore C, Sekelsky J. Drosophila MUS312 and the vertebrate ortholog BTBD12 interact with DNA structure-specific endonucleases in DNA repair and recombination. Mol Cell. 2009;35:128-35 pubmed publisher
    ..Previously, we determined that the Drosophila MEI-9-ERCC1 endonuclease interacts with the MUS312 protein to produce meiotic crossovers, and that MUS312 has a MEI-9-independent role in interstrand crosslink (ICL) ..

More Information

Publications47

  1. Wan B, Yin J, Horvath K, Sarkar J, Chen Y, Wu J, et al. SLX4 assembles a telomere maintenance toolkit by bridging multiple endonucleases with telomeres. Cell Rep. 2013;4:861-9 pubmed publisher
    b>SLX4 interacts with several endonucleases to resolve structural barriers in DNA metabolism. SLX4 also interacts with telomeric protein TRF2 in human cells. The molecular mechanism of these interactions at telomeres remains unknown...
  2. Wilson J, Tejera A, Castor D, Toth R, Blasco M, Rouse J. Localization-dependent and -independent roles of SLX4 in regulating telomeres. Cell Rep. 2013;4:853-60 pubmed publisher
    b>SLX4, a scaffold for structure-specific DNA repair nucleases, is important for several types of DNA repair...
  3. Munoz I, Hain K, Déclais A, Gardiner M, Toh G, Sanchez Pulido L, et al. Coordination of structure-specific nucleases by human SLX4/BTBD12 is required for DNA repair. Mol Cell. 2009;35:116-27 pubmed publisher
    Budding yeast Slx4 interacts with the structure-specific endonuclease Slx1 to ensure completion of ribosomal DNA replication...
  4. Fekairi S, Scaglione S, Chahwan C, Taylor E, Tissier A, Coulon S, et al. Human SLX4 is a Holliday junction resolvase subunit that binds multiple DNA repair/recombination endonucleases. Cell. 2009;138:78-89 pubmed publisher
    ..Here we report the identification of Slx4 orthologs in metazoa, including fly MUS312, essential for meiotic recombination, and human BTBD12, an ATM/ATR checkpoint kinase substrate...
  5. Sobinoff A, Allen J, Neumann A, Yang S, Walsh M, Henson J, et al. BLM and SLX4 play opposing roles in recombination-dependent replication at human telomeres. EMBO J. 2017;36:2907-2919 pubmed publisher
    ..This process is counteracted by the SLX4-SLX1-ERCC4 complex, which promotes resolution of the recombination intermediate, resulting in telomere exchange in ..
  6. González Prieto R, Cuijpers S, Luijsterburg M, van Attikum H, Vertegaal A. SUMOylation and PARylation cooperate to recruit and stabilize SLX4 at DNA damage sites. EMBO Rep. 2015;16:512-9 pubmed publisher
    ..However, whether it is important for interstrand crosslink repair remains unknown. We report that the SLX4 nuclease scaffold protein is regulated by SUMOylation...
  7. Nair N, Castor D, MacArtney T, Rouse J. Identification and characterization of MUS81 point mutations that abolish interaction with the SLX4 scaffold protein. DNA Repair (Amst). 2014;24:131-137 pubmed publisher
    ..In metazoans, a proportion of cellular MUS81-EME1 binds the SLX4 scaffold protein, which is itself instrumental for ICL repair...
  8. Unno J, Itaya A, Taoka M, Sato K, Tomida J, Sakai W, et al. FANCD2 binds CtIP and regulates DNA-end resection during DNA interstrand crosslink repair. Cell Rep. 2014;7:1039-47 pubmed publisher
    ..Collectively, our results reveal a role of monoubiquitinated FANCD2 in end resection that depends on its binding to CtIP during ICL repair...
  9. Shah S, Kim Y, Ostrovnaya I, Murali R, Schrader K, Lach F, et al. Assessment of SLX4 Mutations in Hereditary Breast Cancers. PLoS ONE. 2013;8:e66961 pubmed publisher
    b>SLX4 encodes a DNA repair protein that regulates three structure-specific endonucleases and is necessary for resistance to DNA crosslinking agents, topoisomerase I and poly (ADP-ribose) polymerase (PARP) inhibitors...
  10. Yin J, Wan B, Sarkar J, Horvath K, Wu J, Chen Y, et al. Dimerization of SLX4 contributes to functioning of the SLX4-nuclease complex. Nucleic Acids Res. 2016;44:4871-80 pubmed publisher
    The Fanconi anemia protein SLX4 assembles a genome and telomere maintenance toolkit, consisting of the nucleases SLX1, MUS81 and XPF...
  11. Fugger K, Chu W, Haahr P, Kousholt A, Beck H, Payne M, et al. FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress. Nat Commun. 2013;4:1423 pubmed publisher
    ..Our data suggest that FBH1 helicase activity is required to eliminate cells with excessive replication stress through the generation of MUS81-induced DNA double-strand breaks. ..
  12. Cohen E. From arrest to escape: HIV-1 Vpr cuts a deal. Cell Host Microbe. 2014;15:125-7 pubmed publisher
    ..In a recent issue of Cell, Laguette et al. (2014) demonstrate that untimely activation of the structure-specific endonuclease regulator SLX4 complex by Vpr promotes G2/M arrest and escape from innate immune sensing.
  13. Berger G, Lawrence M, Hué S, Neil S. G2/M cell cycle arrest correlates with primate lentiviral Vpr interaction with the SLX4 complex. J Virol. 2015;89:230-40 pubmed publisher
    ..that human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) mediates this through activation of the SLX4/MUS81/EME1 exonuclease complex that forms part of the Fanconi anemia DNA repair pathway...
  14. Bakker J, van Mil S, Crossan G, Sabbaghian N, De Leeneer K, Poppe B, et al. Analysis of the novel fanconi anemia gene SLX4/FANCP in familial breast cancer cases. Hum Mutat. 2013;34:70-3 pubmed publisher
    SLX4/FANCP is a recently discovered novel disease gene for Fanconi anemia (FA), a rare recessive disorder characterized by chromosomal instability and increased cancer susceptibility...
  15. Gritenaite D, Princz L, Szakal B, Bantele S, Wendeler L, Schilbach S, et al. A cell cycle-regulated Slx4-Dpb11 complex promotes the resolution of DNA repair intermediates linked to stalled replication. Genes Dev. 2014;28:1604-19 pubmed publisher
    ..Central to this regulation is a conserved complex comprising the scaffold proteins Dpb11 and Slx4 that is under stringent control...
  16. Ghosal G, Leung J, Nair B, Fong K, Chen J. Proliferating cell nuclear antigen (PCNA)-binding protein C1orf124 is a regulator of translesion synthesis. J Biol Chem. 2012;287:34225-33 pubmed publisher
    ..Thus, C1orf124 acts at multiple steps in TLS, stabilizes RAD18 and ubiquitinated PCNA at damage sites, and facilitates the switch from replicative to TLS polymerase to bypass DNA lesion. ..
  17. Guenzel C, Hérate C, Benichou S. HIV-1 Vpr-a still "enigmatic multitasker". Front Microbiol. 2014;5:127 pubmed publisher
    ..In this review, we will summarize the main reported functions of HIV-1 Vpr and their significance in the context of the viral life cycle. ..
  18. Guervilly J, Takedachi A, Naim V, Scaglione S, Chawhan C, Lovera Y, et al. The SLX4 complex is a SUMO E3 ligase that impacts on replication stress outcome and genome stability. Mol Cell. 2015;57:123-37 pubmed publisher
    The SLX4 Fanconi anemia protein is a tumor suppressor that may act as a key regulator that engages the cell into specific genome maintenance pathways...
  19. Catucci I, Colombo M, Verderio P, Bernard L, Ficarazzi F, Mariette F, et al. Sequencing analysis of SLX4/FANCP gene in Italian familial breast cancer cases. PLoS ONE. 2012;7:e31038 pubmed publisher
    ..Very recently, SLX4 has been established as a new FA gene raising the question of its implication in breast cancer risk...
  20. Ouyang J, Garner E, Hallet A, Nguyen H, Rickman K, Gill G, et al. Noncovalent interactions with SUMO and ubiquitin orchestrate distinct functions of the SLX4 complex in genome maintenance. Mol Cell. 2015;57:108-22 pubmed publisher
    b>SLX4, a coordinator of multiple DNA structure-specific endonucleases, is important for several DNA repair pathways...
  21. Lachaud C, Castor D, Hain K, Munoz I, Wilson J, MacArtney T, et al. Distinct functional roles for the two SLX4 ubiquitin-binding UBZ domains mutated in Fanconi anemia. J Cell Sci. 2014;127:2811-7 pubmed publisher
    Defects in SLX4, a scaffold for DNA repair nucleases, result in Fanconi anemia (FA), due to the defective repair of inter-strand DNA crosslinks (ICLs)...
  22. Donovan F, Kimble D, Kim Y, Lach F, Harper U, Kamat A, et al. Paternal or Maternal Uniparental Disomy of Chromosome 16 Resulting in Homozygosity of a Mutant Allele Causes Fanconi Anemia. Hum Mutat. 2016;37:465-8 pubmed publisher
    ..FANCA and FANCP/SLX4 genes, both located on chromosome 16, were the affected recessive FA genes in three and one family ..
  23. Pérez Oliva A, Lachaud C, Szyniarowski P, Muñoz I, MacArtney T, Hickson I, et al. USP45 deubiquitylase controls ERCC1-XPF endonuclease-mediated DNA damage responses. EMBO J. 2015;34:326-43 pubmed publisher
    ..Together, these results establish USP45 as a new regulator of XPF-ERCC1 crucial for efficient DNA repair. ..
  24. Liu Q, Underwood T, Kung J, Wang M, Lu H, Paganetti H, et al. Disruption of SLX4-MUS81 Function Increases the Relative Biological Effectiveness of Proton Radiation. Int J Radiat Oncol Biol Phys. 2016;95:78-85 pubmed publisher
    ..We investigated the role of SLX4 (FANCP), which acts as a docking platform for the assembly of multiple structure-specific endonucleases, in the response ..
  25. Fernández Rodríguez J, Quiles F, Blanco I, Teulé A, Feliubadaló L, Valle J, et al. Analysis of SLX4/FANCP in non-BRCA1/2-mutated breast cancer families. BMC Cancer. 2012;12:84 pubmed publisher
    ..Mutations in the SLX4 gene, which encodes for a scaffold protein involved in the repair of interstrand cross-links, have recently been ..
  26. Lilley D. Holliday junction-resolving enzymes-structures and mechanisms. FEBS Lett. 2017;591:1073-1082 pubmed publisher
    ..These complexes are dimerized within the crystal lattice such that the strands of the products may be simply reconnected to form a junction. These structures suggest a trajectory for the resolution process. ..
  27. Fregoso O, Emerman M. Activation of the DNA Damage Response Is a Conserved Function of HIV-1 and HIV-2 Vpr That Is Independent of SLX4 Recruitment. MBio. 2016;7: pubmed publisher
    ..and orthologs, there is a lack of correlation between DNA damage response activation and interaction with the host SLX4 protein complex of structure specific endonucleases; some Vpr proteins are able to interact with SLX4, but the ..
  28. Brégnard C, Benkirane M, Laguette N. DNA damage repair machinery and HIV escape from innate immune sensing. Front Microbiol. 2014;5:176 pubmed publisher
    ..human immunodeficiency virus (HIV), the viral auxiliary protein Vpr activates the structure-specific endonuclease SLX4 complex to promote escape from innate immune sensing and, as a side effect, induces replication stress in cycling ..
  29. Hashimoto K, Wada K, Matsumoto K, Moriya M. Physical interaction between SLX4 (FANCP) and XPF (FANCQ) proteins and biological consequences of interaction-defective missense mutations. DNA Repair (Amst). 2015;35:48-54 pubmed publisher
    SLX4 (FANCP) and XPF (FANCQ) proteins interact with each other and play a vital role in the Fanconi anemia (FA) DNA repair pathway...
  30. Blondot M, Dragin L, Lahouassa H, Margottin Goguet F. How SLX4 cuts through the mystery of HIV-1 Vpr-mediated cell cycle arrest. Retrovirology. 2014;11:117 pubmed publisher
    ..This study highlights for the first time how Vpr recruits the SLX4 endonuclease complex and how Vpr-induced inappropriate activation of this complex leads to G2 arrest...
  31. Kim Y. Nuclease delivery: versatile functions of SLX4/FANCP in genome maintenance. Mol Cells. 2014;37:569-74 pubmed publisher
    As a scaffold, SLX4/FANCP interacts with multiple proteins involved in genome integrity...
  32. de Garibay G, Díaz A, Gaviña B, Romero A, Garre P, Vega A, et al. Low prevalence of SLX4 loss-of-function mutations in non-BRCA1/2 breast and/or ovarian cancer families. Eur J Hum Genet. 2013;21:883-6 pubmed publisher
    ..We address the role of SLX4/FANCP in breast/ovarian cancer susceptibility by conducting a comprehensive mutation scanning in 486 index cases from ..
  33. Schuster B, Knies K, Stoepker C, Velleuer E, Friedl R, Gottwald Mühlhauser B, et al. Whole exome sequencing reveals uncommon mutations in the recently identified Fanconi anemia gene SLX4/FANCP. Hum Mutat. 2013;34:93-6 pubmed publisher
    ..Here, we report on a patient with previously unknown mutations of the most recently identified FA gene, SLX4/FANCP. Whole exome sequencing (WES) revealed a nonsense mutation and an unusual splice site mutation resulting in the ..
  34. Laguette N, Brégnard C, Hue P, Basbous J, Yatim A, Larroque M, et al. Premature activation of the SLX4 complex by Vpr promotes G2/M arrest and escape from innate immune sensing. Cell. 2014;156:134-45 pubmed publisher
    ..we show that G2/M arrest results from untimely activation of the structure-specific endonuclease (SSE) regulator SLX4 complex (SLX4com) by Vpr, a process that requires VPRBP-DDB1-CUL4 E3-ligase complex...
  35. Zhou X, Delucia M, Ahn J. SLX4-SLX1 Protein-independent Down-regulation of MUS81-EME1 Protein by HIV-1 Viral Protein R (Vpr). J Biol Chem. 2016;291:16936-16947 pubmed publisher
    ..structure-selective endonuclease MUS81 forms a complex with EME1 and further associates with another endonuclease SLX4-SLX1 to form a four-subunit complex of MUS81-EME1-SLX4-SLX1, coordinating distinctive biochemical activities of ..
  36. Salewsky B, Schmiester M, Schindler D, Digweed M, Demuth I. The nuclease hSNM1B/Apollo is linked to the Fanconi anemia pathway via its interaction with FANCP/SLX4. Hum Mol Genet. 2012;21:4948-56 pubmed publisher
    ..expressed hSNM1B/Apollo co-immunoprecipitates with SLX4, a protein recently identified as a new FA protein, FANCP, and known to interact with several structure-specific nucleases...