| SLX4IP | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | SLX4IP , C20orf94, bA204H22.1, bA254M13.1, dJ1099D15.3, SLX4 interacting protein | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 615958 MGI: 1921493 HomoloGene: 49913 GeneCards: SLX4IP | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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SLX4 interacting protein is a protein that in humans is encoded by the SLX4IP gene. [5]
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]
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]
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]
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]
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]
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]
RecQ helicase is a family of helicase enzymes initially found in Escherichia coli that has been shown to be important in genome maintenance. They function through catalyzing the reaction ATP + H2O → ADP + P and thus driving the unwinding of paired DNA and translocating in the 3' to 5' direction. These enzymes can also drive the reaction NTP + H2O → NDP + P to drive the unwinding of either DNA or RNA.
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids.
Werner syndrome ATP-dependent helicase, also known as DNA helicase, RecQ-like type 3, is an enzyme that in humans is encoded by the WRN gene. WRN is a member of the RecQ Helicase family. Helicase enzymes generally unwind and separate double-stranded DNA. These activities are necessary before DNA can be copied in preparation for cell division. Helicase enzymes are also critical for making a blueprint of a gene for protein production, a process called transcription. Further evidence suggests that Werner protein plays a critical role in repairing DNA. Overall, this protein helps maintain the structure and integrity of a person's DNA.
In genetics, crosslinking of DNA occurs when various exogenous or endogenous agents react with two nucleotides of DNA, forming a covalent linkage between them. This crosslink can occur within the same strand (intrastrand) or between opposite strands of double-stranded DNA (interstrand). These adducts interfere with cellular metabolism, such as DNA replication and transcription, triggering cell death. These crosslinks can, however, be repaired through excision or recombination pathways.
DNA mismatch repair protein Mlh1 or MutL protein homolog 1 is a protein that in humans is encoded by the MLH1 gene located on chromosome 3. The gene is commonly associated with hereditary nonpolyposis colorectal cancer. Orthologs of human MLH1 have also been studied in other organisms including mouse and the budding yeast Saccharomyces cerevisiae.
Replication protein A 70 kDa DNA-binding subunit is a protein that in humans is encoded by the RPA1 gene.
Mismatch repair endonuclease PMS2 is an enzyme that in humans is encoded by the PMS2 gene.
DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ERCC1 gene. Together with ERCC4, ERCC1 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.
Bloom syndrome protein is a protein that in humans is encoded by the BLM gene and is not expressed in Bloom syndrome.
Exonuclease 1 is an enzyme that in humans is encoded by the EXO1 gene.
ERCC4 is a protein designated as DNA repair endonuclease XPF that in humans is encoded by the ERCC4 gene. Together with ERCC1, ERCC4 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.
DNA repair and recombination protein RAD54-like is a protein that in humans is encoded by the RAD54L gene.
Crossover junction endonuclease MUS81 is an enzyme that in humans is encoded by the MUS81 gene.
DNA mismatch repair protein Mlh3 is a protein that in humans is encoded by the MLH3 gene.
DNA cross-link repair 1A protein is a protein that in humans is encoded by the DCLRE1A gene.
DNA cross-link repair 1B protein is a protein that in humans is encoded by the DCLRE1B gene.
Fanconi anemia, complementation group M, also known as FANCM is a human gene. It is an emerging target in cancer therapy, in particular cancers with specific genetic deficiencies.
SLX4 is a protein involved in DNA repair, where it has important roles in the final steps of homologous recombination. Mutations in the gene are associated with the disease Fanconi anemia.
Telomere-binding proteins function to bind telomeric DNA in various species. In particular, telomere-binding protein refers to TTAGGG repeat binding factor-1 (TERF1) and TTAGGG repeat binding factor-2 (TERF2). Telomere sequences in humans are composed of TTAGGG sequences which provide protection and replication of chromosome ends to prevent degradation. Telomere-binding proteins can generate a T-loop to protect chromosome ends. TRFs are double-stranded proteins which are known to induce bending, looping, and pairing of DNA which aids in the formation of T-loops. They directly bind to TTAGGG repeat sequence in the DNA. There are also subtelomeric regions present for regulation. However, in humans, there are six subunits forming a complex known as shelterin.
GEN1, Holliday junction 5' flap endonuclease is a protein that in humans is encoded by the GEN1 gene.
