SETMAR

SETMAR contains a SET domain that confers its histone methyltransferase activity, on Lys-4 and Lys-36 of Histone H3, both of which are specific tags for epigenetic activation. It has been identified as a repair protein as it mediates dimethylation at Lys-36 at double-strand break locations, a signal enhancing NHEJ repair.[7][8]

Anthropoid primates, including humans, have a version of the protein fused to a Mariner/Tc1 transposase. This fusion region provides the DNA-binding abilities for the protein as well as some nuclease activity. The transposase activity is lost due to the presence of several inactivating mutations,[9] including the D610N mutation.[10][11] However, the domesticated transposase domain retains its ability to bind to the mariner repeat elements in the genome.[12][13][14][15] SETMAR has been found to affect the expression and splicing of genes close to or containing mariner repeat elements via its functions in histone methylation.[12][13][15] Both the SET, via its methyltransferase activity,[7][8][16] and the mariner, with its DNA-binding [17] and nuclease activities,[18][19][20][21][16] domains of SETMAR have been shown to act in non-homologous end joining (NHEJ) to repair DNA double strand breaks.

Model organisms have been used in the study of SETMAR function. A conditional knockout mouse line, called Setmar^{tm1a(EUCOMM)Wtsi}[28][29] 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.[30][31][32] Note that the mouse ortholog is does not have the Tc1/mariner ("MAR") fusion; such a fusion is found only in anthropoid primates. Therefore, the knockout mouse is not for SETMAR but only the SET domain of this chimeric fusion protein.

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[26][33] Twenty five tests were carried out on mutant mice and two significant abnormalities were observed.[26] Homozygous mutant animals of both sex had abnormal retinal pigmentation and morphology, while males also had atypical peripheral blood lymphocyte parameters.[26]