Abstract
SETMAR is a fusion between a SET-domain methyltransferase gene and a mariner-family transposase gene, which is specific to anthropoid primates. However, the ancestral SET gene is present in all other mammals and birds. SETMAR is reported to be involved in transcriptional regulation and a diverse set of reactions related to DNA repair. Since the transcriptional effects of SETMAR depend on site-specific DNA binding, and are perturbed by inactivating the methyltransferase, we wondered whether we could differentiate the effects of the SET and MAR domains in DNA repair assays. We therefore generated several stable U2OS cell lines expressing either wild type SETMAR or truncation or point mutant variants. We tested these cell lines with in vivo plasmid-based assays to determine the relevance of the different domains and activities of SETMAR in DNA repair. Contrary to previous reports, we found that wild type SETMAR had little to no effect on the rate of cell division, DNA integration into the genome or non-homologous end joining. Also contrary to previous reports, we failed to detect any effect of a strong active-site mutation that should have knocked out the putative nuclease activity of SETMAR.
Highlights
SETMAR is an anthropoid primate-specific fusion between a histone methyltransferase, which dimethylates histone H3 lysine 36 (H3K36me2), and a domesticated Hsmar1 transposase [1,2,3]
We previously demonstrated that modest, stable, overexpression of SETMAR in a U2OS cell line significantly changed the expression of a large set of genes, and that this depended on the DNA binding and methyltransferase activities [7]
To determine whether altering SETMAR expression level affects the growth rate of the U2OS cell line, we tested three stable TRex-U2OS cell lines overexpressing SETMAR at different levels, together with one cell line expressing the SET domain only and a parental cell line with an empty expression vector integrated in its genome (Fig. 2A)
Summary
SETMAR is an anthropoid primate-specific fusion between a histone methyltransferase, which dimethylates histone H3 lysine 36 (H3K36me2), and a domesticated Hsmar transposase [1,2,3]. The transposase domain of SETMAR retains its ability to dimerize and bind transposon ends [2,4,7]. The pattern of transcriptional-changes induced by SETMAR expression depended on the methyltransferase and its site specific DNA binding to the Hsmar transposon ends scattered throughout the human genome [7]. This supports the hypothesis that the DNA binding domain of SETMAR serves to target the methylase to a subset of the Hsmar transposon ends dispersed throughout the human genome [2]
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