SLX4

SLX4 (also known as BTBD12 and FANCP) is a is_associated_with::protein involved in is_associated_with::DNA repair, where it has important roles in the final steps of is_associated_with::homologous recombination. Mutations in the gene are associated with the disease is_associated_with::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 is_associated_with::multiprotein complexes. The is_associated_with::SLX1-SLX4 complex acts as a is_associated_with::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, is_associated_with::RAD10 and SAW1 in the single-strand annealing pathway of homologous recombination.

Model organisms
is_associated_with::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 is_associated_with::Sgs1 protein. Based on that, SLX4 was grouped with several other proteins produced by SLX (synthetic lethal of unknown function) genes.

A conditional is_associated_with::knockout mouse line, called Slx4tm1a(EUCOMM)Wtsi was generated as part of the is_associated_with::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 is_associated_with::phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on is_associated_with::mutant mice and ten significant abnormalities were observed. A viability at weaning study found less is_associated_with::homozygous is_associated_with::mutant animals were present than predicted by is_associated_with::Mendelian ratio. Homozygous mutant animals of both sexes were sub-fertile and homozygous females had a reduced body weight, body length, heart weight, is_associated_with::platelet count and is_associated_with::lean mass. Homozygotes of both sex had abnormal eye sizes, narrow eye openings, skeletal defects (including is_associated_with::scoliosis and fusion of vertebrae), and displayed an increase in DNA instability as shown by a is_associated_with::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.