SLX4IP

SLX4 interacting protein is a protein that in humans is encoded by the SLX4IP gene.^[5]

SLX4IP
Identifiers
Aliases	SLX4IP, C20orf94, bA204H22.1, bA254M13.1, dJ1099D15.3, SLX4 interacting protein
External IDs	OMIM: 615958; MGI: 1921493; HomoloGene: 49913; GeneCards: SLX4IP; OMA:SLX4IP - orthologs
Gene location (Human) Chr. Chromosome 20 (human)[1] Band 20p12.2 Start 10,435,305 bp[1] End 10,636,829 bp[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band 2|2 F3 Start 136,733,138 bp[2] End 136,913,870 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in pancreatic epithelial cell pancreatic ductal cell corpus epididymis oocyte secondary oocyte nasal epithelium sperm epithelium of nasopharynx gums gingival epithelium Top expressed in zygote secondary oocyte hand spermatocyte tail of embryo genital tubercle Rostral migratory stream primary oocyte ganglionic eminence epiblast More reference expression data BioGPS n/a
Orthologs Species Human Mouse Entrez 128710 74243 Ensembl ENSG00000149346 ENSMUSG00000027281 UniProt Q5VYV7 Q9D7Y9 RefSeq (mRNA) NM_001009608 NM_001038641 NM_028201 NM_028834 NM_001355669 NM_001355670 NM_001355671 RefSeq (protein) NP_001009608 NP_001033730 NP_082477 NP_083110 NP_001342598 NP_001342599 NP_001342600 Location (UCSC) Chr 20: 10.44 – 10.64 Mb Chr 2: 136.73 – 136.91 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.^[6]

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.^[7]

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.^[8]

Location and expression

The SLX4IP gene is located on the short arm (p) of chromosome 20 at position 12.2 (20p12.2).^[9] The human SLX4IP gene contains 14 exons, with the cDNA being 204,000 base pairs orientated on the plus strand.^[9] This codes for a protein of 408 amino acids with a molecular mass of 45,552 daltons.^[10]

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.^[11] Orthologs for the human SLX4IP gene have also been identified in 283 other organisms.^[11]

The SLX4IP protein is expressed at its highest level in the skin and the testis, along with being expressed in 26 other tissues.^[12]

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.^[13] By analyzing the breakpoints of SLX4IP, characteristic illegitimate V(D)J mediated recombination was revealed.^[13] These deletions were found to be significantly biased towards the male gender.^[13]

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).^[14] This recombination has been shown to require the accumulation of SLX4IP at ALT telomeres due to its antagonization of promiscuous BLM activity.^[8] BLM is responsible for the extension of telomeres as it is a RecQ helicase vital to homologous recombination and DNA replication.^[15]

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.^[16] 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.^[6][17] 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.^[17][18]

HIV-1

The HIV-1 auxiliary protein Vpr potently stops the host cells progression through its natural cycle at the G2/M transition stage.^[19] This arrest was found to be caused from its premature activation of the SLX4 structure-specific endonuclease complex, which SLX4IP directly interacts with.^[20] 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.^[20]

References

1. GRCh38: Ensembl release 89: ENSG00000149346 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000027281 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: SLX4 interacting protein".
6. Svendsen JM, Smogorzewska A, Sowa ME, O'Connell BC, Gygi SP, Elledge SJ, Harper JW (July 2009). "Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is required for DNA repair". Cell. 138 (1): 63–77. doi:10.1016/j.cell.2009.06.030. PMC 2720686. PMID 19596235.
7. Fekairi S, Scaglione S, Chahwan C, Taylor ER, Tissier A, Coulon S, et al. (July 2009). "Human SLX4 is a Holliday junction resolvase subunit that binds multiple DNA repair/recombination endonucleases". Cell. 138 (1): 78–89. doi:10.1016/j.cell.2009.06.029. PMC 2861413. PMID 19596236.
8. Panier S, Maric M, Hewitt G, Mason-Osann E, Gali H, Dai A, et al. (October 2019). "SLX4IP Antagonizes Promiscuous BLM Activity during ALT Maintenance". Molecular Cell. 76 (1): 27–43.e11. doi:10.1016/j.molcel.2019.07.010. PMC 6863466. PMID 31447390.
9. "SLX4IP SLX4 interacting protein [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2019-10-31.
10. "SLX4IP - Protein SLX4IP - Homo sapiens (Human) - SLX4IP gene & protein". www.uniprot.org. Retrieved 2019-10-31.
11. "Gene: SLX4IP (ENSG00000149346) - Summary - Homo sapiens - Ensembl genome browser 98". asia.ensembl.org. Retrieved 2019-10-31.
12. Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, et al. (February 2014). "Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics". Molecular & Cellular Proteomics. 13 (2): 397–406. doi:10.1074/mcp.M113.035600. PMC 3916642. PMID 24309898.
13. Meissner B, Bartram T, Eckert C, Trka J, Panzer-Grümayer R, Hermanova I, et al. (February 2014). "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. doi:10.1093/hmg/ddt447. PMID 24045615.
14. Bryan TM, Englezou A, Dalla-Pozza L, Dunham MA, Reddel RR (November 1997). "Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines". Nature Medicine. 3 (11): 1271–4. doi:10.1038/nm1197-1271. PMID 9359704. S2CID 10220776.
15. Bhattacharyya S, Keirsey J, Russell B, Kavecansky J, Lillard-Wetherell K, Tahmaseb K, et al. (May 2009). "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. doi:10.1074/jbc.m900195200. PMC 2685679. PMID 19329795.
16. Hashimoto S, Anai H, Hanada K (2016-05-01). "Mechanisms of interstrand DNA crosslink repair and human disorders". Genes and Environment. 38 (1): 9. Bibcode:2016GeneE..38....9H. doi:10.1186/s41021-016-0037-9. PMC 4918140. PMID 27350828.
17. Zhang H, Chen Z, Ye Y, Ye Z, Cao D, Xiong Y, et al. (November 2019). "SLX4IP acts with SLX4 and XPF-ERCC1 to promote interstrand crosslink repair". Nucleic Acids Research. 47 (19): 10181–10201. doi:10.1093/nar/gkz769. PMC 6821277. PMID 31495888.
18. McHugh PJ, Sarkar S (May 2006). "DNA interstrand cross-link repair in the cell cycle: a critical role for polymerase zeta in G1 phase". Cell Cycle. 5 (10): 1044–7. doi:10.4161/cc.5.10.2763. PMID 16687932.
19. Connor RI, Chen BK, Choe S, Landau NR (February 1995). "Vpr is required for efficient replication of human immunodeficiency virus type-1 in mononuclear phagocytes". Virology. 206 (2): 935–44. doi:10.1006/viro.1995.1016. PMID 7531918.
20. Laguette N, Brégnard C, Hue P, Basbous J, Yatim A, Larroque M, et al. (January 2014). "Premature activation of the SLX4 complex by Vpr promotes G2/M arrest and escape from innate immune sensing". Cell. 156 (1–2): 134–45. doi:10.1016/j.cell.2013.12.011. PMID 24412650.

Further reading

• Svendsen JM, Smogorzewska A, Sowa ME, O'Connell BC, Gygi SP, Elledge SJ, Harper JW (July 2009). "Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is required for DNA repair". Cell. 138 (1): 63–77. doi:10.1016/j.cell.2009.06.030. PMC 2720686. PMID 19596235.
• Ghosal G, Leung JW, Nair BC, Fong KW, Chen J (October 2012). "Proliferating cell nuclear antigen (PCNA)-binding protein C1orf124 is a regulator of translesion synthesis". The Journal of Biological Chemistry. 287 (41): 34225–33. doi:10.1074/jbc.M112.400135. PMC 3464530. PMID 22902628.
• Warnatz HJ, Schmidt D, Manke T, Piccini I, Sultan M, Borodina T, et al. (July 2011). "The BTB and CNC homology 1 (BACH1) target genes are involved in the oxidative stress response and in control of the cell cycle". The Journal of Biological Chemistry. 286 (26): 23521–32. doi:10.1074/jbc.M111.220178. PMC 3123115. PMID 21555518.