SLX4
SLX4 (also known as BTBD12 and FANCP) is a protein involved in DNA repair, where it has important roles in the final steps of homologous recombination.[5] Mutations in the gene are associated with the disease Fanconi anemia.[6][7]
The version of SLX4 present in humans and other mammals acts as a sort of scaffold upon which other proteins form several different multiprotein complexes. The SLX1-SLX4 complex acts as a Holliday junction resolvase. As such, the complex cleaves the links between two homologous chromosomes that form during homologous recombination. This allows the two linked chromosomes to resolve into two unconnected double-strand DNA molecules.[8] SLX4 also associates with RAD1, RAD10 and SAW1 in the single-strand annealing pathway of homologous recombination.[9]
Model organisms
Model organisms have been prominent in the study of SLX4 function. It was identified in 2001 during a screen for lethal mutations in yeast cells lacking a functional copy of the Sgs1 protein. Based on that, SLX4 was grouped with several other proteins produced by SLX (synthetic lethal of unknown function) genes.[10]
| Characteristic | Phenotype |
|---|---|
| Homozygote viability | Abnormal |
| Fertility | Abnormal |
| Body weight | Abnormal[11] |
| Anxiety | Normal |
| Neurological assessment | Normal |
| Grip strength | Normal |
| Hot plate | Normal |
| Dysmorphology | Abnormal[12] |
| Indirect calorimetry | Normal |
| Glucose tolerance test | Normal |
| Auditory brainstem response | Normal |
| DEXA | Abnormal[13] |
| Radiography | Abnormal[14] |
| Body temperature | Normal |
| Eye morphology | Abnormal[15] |
| Clinical chemistry | Normal |
| Haematology | Abnormal[16] |
| Peripheral blood lymphocytes | Normal |
| Micronucleus test | Abnormal |
| Heart weight | Abnormal[17] |
| Skin Histopathology | Normal |
| Brain histopathology | Normal |
| Salmonella infection | Normal[18] |
| Citrobacter infection | Normal[19] |
| All tests and analysis from[20][21] |
A conditional knockout mouse line, called Slx4tm1a(EUCOMM)Wtsi[22] was generated as part of the International Knockout Mouse Consortium program, a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[23][24][25]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[7][20] Twenty four tests were carried out on mutant mice and ten significant abnormalities were observed.[20] A viability at weaning study found less homozygous mutant animals were present than predicted by Mendelian ratio. Homozygous mutant animals of both sexes were sub-fertile and homozygous females had a reduced body weight, body length, heart weight, platelet count and lean mass.[26] Homozygotes of both sex had abnormal eye sizes, narrow eye openings, skeletal defects (including scoliosis and fusion of vertebrae), and displayed an increase in DNA instability as shown by a micronucleus test.[20] This and further analysis revealed the mouse phenotype to model the human genetic illness, Fanconi anemia.[7][26] The association was confirmed when patients with the disease were found to have mutations in their SLX4 gene.[6]
References
- 1 2 3 GRCh38: Ensembl release 89: ENSG00000188827 - Ensembl, May 2017
- 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000039738 - Ensembl, May 2017
- ↑ "Human PubMed Reference:".
- ↑ "Mouse PubMed Reference:".
- ↑ Klein, HL; Symington, LS (10 July 2009). "Breaking up just got easier to do". Cell. 138 (1): 20–22. PMID 19596231. doi:10.1016/j.cell.2009.06.039.
- 1 2 Kim Y; Lach FP; Desetty R; Hanenberg H; Auerbach AD; Smogorzewska A (February 2011). "Mutations of the SLX4 gene in Fanconi anemia". Nat. Genet. 43 (2): 142–6. PMC 3345287
. PMID 21240275. doi:10.1038/ng.750. - 1 2 3 van der Weyden L; White JK; Adams DJ; Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism.". Genome Biol. 12 (6): 224. PMC 3218837 . PMID 21722353. doi:10.1186/gb-2011-12-6-224.
- ↑ Svendsen, JM; et al. (10 July 2009). "Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is required for DNA repair". Cell. 138 (1): 63–77. PMC 2720686 . PMID 19596235. doi:10.1016/j.cell.2009.06.030.
- ↑ Mimitou, EP; Symington, LS (2 September 2009). "DNA end resection: Many nucleases make light work". DNA repair. 8 (9): 983–995. PMC 2760233 . PMID 19473888. doi:10.1016/j.dnarep.2009.04.017.
- ↑ Mullen, JR; et al. (January 2001). "Requirement for three novel protein complexes in the absence of the Sgs1 DNA helicase in Saccharomyces cerevisiae". Genetics. 157 (1): 103–118. PMC 1461486 . PMID 11139495.
- ↑ "Body weight data for Slx4". Wellcome Trust Sanger Institute.
- ↑ "Dysmorphology data for Slx4". Wellcome Trust Sanger Institute.
- ↑ "DEXA data for Slx4". Wellcome Trust Sanger Institute.
- ↑ "Radiography data for Slx4". Wellcome Trust Sanger Institute.
- ↑ "Eye morphology data for Slx4". Wellcome Trust Sanger Institute.
- ↑ "Haematology data for Slx4". Wellcome Trust Sanger Institute.
- ↑ "Heart weight data for Slx4". Wellcome Trust Sanger Institute.
- ↑ "Salmonella infection data for Slx4". Wellcome Trust Sanger Institute.
- ↑ "Citrobacter infection data for Slx4". Wellcome Trust Sanger Institute.
- 1 2 3 4 Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88 (S248). doi:10.1111/j.1755-3768.2010.4142.x.
- ↑ Mouse Resources Portal, Wellcome Trust Sanger Institute.
- ↑ "International Knockout Mouse Consortium".
- ↑ Skarnes, W. C.; Rosen, B.; West, A. P.; Koutsourakis, M.; Bushell, W.; Iyer, V.; Mujica, A. O.; Thomas, M.; Harrow, J.; Cox, T.; Jackson, D.; Severin, J.; Biggs, P.; Fu, J.; Nefedov, M.; De Jong, P. J.; Stewart, A. F.; Bradley, A. (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–342. PMC 3572410 . PMID 21677750. doi:10.1038/nature10163.
- ↑ Dolgin E (June 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. PMID 21677718. doi:10.1038/474262a.
- ↑ Collins FS; Rossant J; Wurst W (January 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. PMID 17218247. doi:10.1016/j.cell.2006.12.018.
- 1 2 Crossan GP, van der Weyden L, Rosado IV, et al. (February 2011). "Disruption of mouse Slx4, a regulator of structure-specific nucleases, phenocopies Fanconi anemia". Nat. Genet. 43 (2): 147–52. PMC 3624090 . PMID 21240276. doi:10.1038/ng.752.