SLX4IP explained

SLX4 interacting protein is a protein that in humans is encoded by the SLX4IP gene.[1]

Function

SLX4 interacting protein (SLX4IP) exists in a monomeric form, and interacts with the SLX4-XPF-ERCC1 multiprotein complex, which is responsible for the assembly of a Holliday junction resolvase in the role of DNA repair and maintenance.[2]

SLX4IP has been shown to directly interact with the N-terminal end of the SLX4 protein, which plays a role in the coordination of multiple different DNA structure-specific endonucleases.[3]

SLX4IP has also been shown to be involved in the control of alternative lengthening of telomeres, through its accumulation and interactions with the SLX4, BLM and XPF proteins.[4]

Location and expression

The SLX4IP gene is located on the short arm (p) of chromosome 20 at position 12.2 (20p12.2).[5] The human SLX4IP gene contains 14 exons, with the cDNA being 204,000 base pairs orientated on the plus strand. This codes for a protein of 408 amino acids with a molecular mass of 45,552 daltons.[6]

Homologs of the SLX4IP gene have been found to be conserved in several non-human species including mice, rats, frogs, chickens, dogs, rhesus monkeys and chimpanzees.[7] Orthologs for the human SLX4IP gene have also been identified in 283 other organisms.

The SLX4IP protein is expressed at its highest level in the skin and the testis, along with being expressed in 26 other tissues.[8]

Clinical significance

Cancer

Acute lymphoblastic leukemia

Somatic and monoallelic deletions of the 5’ region of SLX4IP was shown to occur in 30% of patients with childhood acute lymphoblastic leukemia (ALL) and in cases of ETV6/RUNX1-rearranged acute lymphoblastic leukemia, deletions were found in greater than 60% of cases.[9] By analyzing the breakpoints of SLX4IP, characteristic illegitimate V(D)J mediated recombination was revealed. These deletions were found to be significantly biased towards the male gender.[9]

Alternative lengthening of telomeres

In order for cancer cells to retain their ability to proliferate without limitations, they can regulate the telomeres of their chromosomes by recombination via a process known as alternative lengthening of telomeres (ALT).[10] This recombination has been shown to require the accumulation of SLX4IP at ALT telomeres due to its antagonization of promiscuous BLM activity. BLM is responsible for the extension of telomeres as it is a RecQ helicase vital to homologous recombination and DNA replication.[11]

Interstrand crosslink repair

In DNA, Interstrand crosslinks (ICLs) are required to be repaired due to their high toxicity, often leading to diseases such as Fanconi anaemia.[12] SLX4IP plays a role in the ICL repair functionality of the SLX4-XPF-ERCC1 complex, due to its simultaneous binding of both SLX4 and XPF-ERCC1, which maintains the stability of the complex and promotes interaction between the SLX4 and the XPF-ERCC1 regions.[13] When SLX4IP was depleted from treated cells, they were found to accumulate in the G2/M phase of the cell cycle where the resolution of holiday junctions during ICL repair regularly occurs.[14]

HIV-1

The HIV-1 auxiliary protein Vpr potently stops the host cells progression through its natural cycle at the G2/M transition stage.[15] This arrest was found to be caused from its premature activation of the SLX4 structure-specific endonuclease complex, which SLX4IP directly interacts with.[16] Through this research the SLX4 complex was also discovered to be involved with the regulation of innate immunity, due to its negative regulation of type 1 interferon production, both when induced spontaneously and HIV-1-mediated.

Further reading

Notes and References

  1. Web site: Entrez Gene: SLX4 interacting protein .
  2. Svendsen JM, Smogorzewska A, Sowa ME, O'Connell BC, Gygi SP, Elledge SJ, Harper JW . Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is required for DNA repair . Cell . 138 . 1 . 63–77 . July 2009 . 19596235 . 2720686 . 10.1016/j.cell.2009.06.030 .
  3. Fekairi S, Scaglione S, Chahwan C, Taylor ER, Tissier A, Coulon S, Dong MQ, Ruse C, Yates JR, Russell P, Fuchs RP, McGowan CH, Gaillard PH . 6 . Human SLX4 is a Holliday junction resolvase subunit that binds multiple DNA repair/recombination endonucleases . Cell . 138 . 1 . 78–89 . July 2009 . 19596236 . 2861413 . 10.1016/j.cell.2009.06.029 .
  4. Panier S, Maric M, Hewitt G, Mason-Osann E, Gali H, Dai A, Labadorf A, Guervilly JH, Ruis P, Segura-Bayona S, Belan O, Marzec P, Gaillard PL, Flynn RL, Boulton SJ . 6 . SLX4IP Antagonizes Promiscuous BLM Activity during ALT Maintenance . Molecular Cell . 76 . 1 . 27–43.e11 . October 2019 . 31447390 . 10.1016/j.molcel.2019.07.010 . 6863466 .
  5. Web site: SLX4IP SLX4 interacting protein [Homo sapiens (human)] - Gene - NCBI]. www.ncbi.nlm.nih.gov. 2019-10-31.
  6. Web site: SLX4IP - Protein SLX4IP - Homo sapiens (Human) - SLX4IP gene & protein. www.uniprot.org. 2019-10-31.
  7. Web site: Gene: SLX4IP (ENSG00000149346) - Summary - Homo sapiens - Ensembl genome browser 98. asia.ensembl.org. 2019-10-31.
  8. Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, Habuka M, Tahmasebpoor S, Danielsson A, Edlund K, Asplund A, Sjöstedt E, Lundberg E, Szigyarto CA, Skogs M, Takanen JO, Berling H, Tegel H, Mulder J, Nilsson P, Schwenk JM, Lindskog C, Danielsson F, Mardinoglu A, Sivertsson A, von Feilitzen K, Forsberg M, Zwahlen M, Olsson I, Navani S, Huss M, Nielsen J, Ponten F, Uhlén M . 6 . Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics . Molecular & Cellular Proteomics . 13 . 2 . 397–406 . February 2014 . 24309898 . 3916642 . 10.1074/mcp.M113.035600 . free .
  9. Meissner B, Bartram T, Eckert C, Trka J, Panzer-Grümayer R, Hermanova I, Ellinghaus E, Franke A, Möricke A, Schrauder A, Teigler-Schlegel A, Dörge P, von Stackelberg A, Basso G, Bartram CR, Kirschner-Schwabe R, Bornhäuser B, Bourquin JP, Cazzaniga G, Hauer J, Attarbaschi A, Izraeli S, Zaliova M, Cario G, Zimmermann M, Avigad S, Sokalska-Duhme M, Metzler M, Schrappe M, Koehler R, Te Kronnie G, Stanulla M . 6 . Frequent and sex-biased deletion of SLX4IP by illegitimate V(D)J-mediated recombination in childhood acute lymphoblastic leukemia . Human Molecular Genetics . 23 . 3 . 590–601 . February 2014 . 24045615 . 10.1093/hmg/ddt447 . free .
  10. Bryan TM, Englezou A, Dalla-Pozza L, Dunham MA, Reddel RR . Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines . Nature Medicine . 3 . 11 . 1271–4 . November 1997 . 9359704 . 10.1038/nm1197-1271 . 10220776 .
  11. Bhattacharyya S, Keirsey J, Russell B, Kavecansky J, Lillard-Wetherell K, Tahmaseb K, Turchi JJ, Groden J . 6 . Telomerase-associated protein 1, HSP90, and topoisomerase IIalpha associate directly with the BLM helicase in immortalized cells using ALT and modulate its helicase activity using telomeric DNA substrates . The Journal of Biological Chemistry . 284 . 22 . 14966–77 . May 2009 . 19329795 . 10.1074/jbc.m900195200 . 2685679 . free .
  12. Hashimoto S, Anai H, Hanada K . Mechanisms of interstrand DNA crosslink repair and human disorders . Genes and Environment . 38 . 1 . 9 . 2016-05-01 . 27350828 . 4918140 . 10.1186/s41021-016-0037-9 . 2016GeneE..38....9H . free .
  13. Zhang H, Chen Z, Ye Y, Ye Z, Cao D, Xiong Y, Srivastava M, Feng X, Tang M, Wang C, Tainer JA, Chen J . 6 . SLX4IP acts with SLX4 and XPF-ERCC1 to promote interstrand crosslink repair . Nucleic Acids Research . 47 . 19 . 10181–10201 . November 2019 . 31495888 . 10.1093/nar/gkz769 . 6821277 .
  14. McHugh PJ, Sarkar S . DNA interstrand cross-link repair in the cell cycle: a critical role for polymerase zeta in G1 phase . Cell Cycle . 5 . 10 . 1044–7 . May 2006 . 16687932 . 10.4161/cc.5.10.2763 . free .
  15. Connor RI, Chen BK, Choe S, Landau NR . Vpr is required for efficient replication of human immunodeficiency virus type-1 in mononuclear phagocytes . Virology . 206 . 2 . 935–44 . February 1995 . 7531918 . 10.1006/viro.1995.1016 . free .
  16. Laguette N, Brégnard C, Hue P, Basbous J, Yatim A, Larroque M, Kirchhoff F, Constantinou A, Sobhian B, Benkirane M . 6 . Premature activation of the SLX4 complex by Vpr promotes G2/M arrest and escape from innate immune sensing . Cell . 156 . 1–2 . 134–45 . January 2014 . 24412650 . 10.1016/j.cell.2013.12.011 . free .

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