SCAN/KRAB

The SCAN/KRAB cellular integrases (C-INTs) are two intron-exon structured host gene paralogs of the eutherian genomes, which split into two variants (formally called ZNF452/SCAND3 (of approximately 1,300 residues) and KRBA2 (460-500 residues) according to the Genbank nomenclature (Benson et al. 2010). ZNF452/SCAND3 shows at its N-terminus, a dimerization SCAN domain involved in transcriptional regulation of growth factors and genes involved in metabolism, cell survival and differentiation (Sander et al. 2003; Collins & Sander 2010), as well as a hATd dimerization domain similar to that of the TR activator superfamily (Rubin et al. 2001) at its C-terminus. In turn, the KRBA2 variant lacks the hATd domain and substitutes the SCAN domain by a module called Krüppel-associated box (KRAB) domain (Bellefroid et al. 1991; Lander et al. 2001; Venter et al. 2001), a gene expression repressor motif involved in maintenance of the nucleolus, cell differentiation, cell proliferation, apoptosis, and neoplastic transformation (Bellefroid et al. 1991; Lander et al. 2001; Venter et al. 2001). For simplicity´s sake the figure below shows the genomic structure of each variant without introns.

While the original notion in the origin of SCAN/KRAB C-INTs is that they might me related to the Integrases (INTs) of LTR retroelements or with the transposases (TRs) coded by the Maverick/Polinton transposons (Gao & Voytas 2005; Feschotte & Pritham 2005; Pritham et al. 2007), recent research has revealed that SCAN/KRAB C-INTs unequivocally evolve from the domestication of a GINGER2 transposon, which probably was horizontally transferred from insects to the eutherians after to the methaterian-eutherian (Llorens et al. submitted).

There are three complementary classifications for SCAN/KRAB C-INTs. Based on sequence these enzymes can be classified as DDE TRs and INTs. Based on INT-like structural potential similarities, SCAN/KRAB C-INTs are members of the Retroviral Integrase Superfamily (Nowotny 2009) of nucleic acid-processing enzymes involved in; a) selfish evolution; b) replication and repair of DNA; c) recombination and gene fusion; d) RNA-mediated gene silencing; and e) oncogenesis. Based on the presence of additional SCAN/KRAB domains these enzymes can be classified as chimeric members of the SCAN superfamily of zinc finger transcription factors (Sander et al. 2003; Collins & Sander 2010).