SLX4

SLX4 structure-specific endonuclease subunit
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 4M7C, 4UYI
Identifiers
Symbols	SLX4 ; BTBD12; FANCP; MUS312
External IDs	OMIM: 613278 HomoloGene: 23770 GeneCards: SLX4 Gene
Gene ontology Molecular function • protein binding • enzyme activator activity • crossover junction endodeoxyribonuclease activity • 5'-flap endonuclease activity • 3'-flap endonuclease activity Cellular component • nuclear chromosome, telomeric region • nuclear chromatin • nucleoplasm • cytoplasm • cell junction • Slx1-Slx4 complex • Holliday junction resolvase complex • ERCC4-ERCC1 complex Biological process • double-strand break repair via homologous recombination • DNA replication • DNA repair • nucleotide-excision repair • DNA double-strand break processing involved in repair via single-strand annealing • positive regulation of catalytic activity • response to intra-S DNA damage checkpoint signaling Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	84464	52864
Ensembl	ENSG00000188827	ENSMUSG00000039738
UniProt	Q8IY92	Q6P1D7
RefSeq (mRNA)	NM_032444	NM_177472
RefSeq (protein)	NP_115820	NP_803423
Location (UCSC)	Chr 16: 3.58 – 3.61 Mb	Chr 16: 3.98 – 4 Mb
PubMed search	[1]	[2]

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. Mutations in the gene are associated with the disease Fanconi anemia.

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. SLX4 also associates with RAD1, RAD10 and SAW1 in the single-strand annealing pathway of homologous recombination.

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.

Slx4 knockout mouse phenotype

Characteristic	Phenotype
Homozygote viability	Abnormal
Fertility	Abnormal
Body weight	Abnormal
Anxiety	Normal
Neurological assessment	Normal
Grip strength	Normal
Hot plate	Normal
Dysmorphology	Abnormal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Abnormal
Radiography	Abnormal
Body temperature	Normal
Eye morphology	Abnormal
Clinical chemistry	Normal
Haematology	Abnormal
Peripheral blood lymphocytes	Normal
Micronucleus test	Abnormal
Heart weight	Abnormal
Skin Histopathology	Normal
Brain histopathology	Normal
Salmonella infection	Normal
Citrobacter infection	Normal
All tests and analysis from

A conditional knockout mouse line, called Slx4^{tm1a(EUCOMM)Wtsi} 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.

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on mutant mice and ten significant abnormalities were observed. 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. 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. This and further analysis revealed the mouse phenotype to model the human genetic illness, Fanconi anemia. The association was confirmed when patients with the disease were found to have mutations in their SLX4 gene.