The DUF3715 domain has a conserved role in RNA-directed transposon silencing

RNA-directed transposon silencing operates in the mammalian soma and germline tosafeguard genomic integrity. The piRNA pathway and the HUSHcomplex identify activetransposons through recognition of their nascent transcripts, but mechanisticunderstanding of how these distinct pathways evolved is lacking. TASOR is anessential component of the HUSH complex. TASOR's DUF3715 domain adopts apseudo-PARP structure and is required for transposon silencing in a mannerindependent of complex assembly. TEX15, an essential piRNA pathway factor, alsocontains the DUF3715 domain. Here, we show that TASOR's and TEX15's DUF3715domain share extensive structural homology. We found that the DUF3715 domain arosein early eukaryotes and that in vertebrates it is restricted to TEX15, TASOR, andTASORB orthologues. While TASOR-like proteins are found throughout metazoa,TEX15 is vertebrate specific. The branchingof TEX15 and TASOR-like DUF3715 domainlikely occurred in early metazoan evolution. Remarkably, despite this vast evolutionarydistance, the DUF3715 domain from divergent TEX15 sequences can functionallysubstitute for the same domain in TASOR and mediates transposon silencing. We havethus termed this domain of unknown function as the RNA-directed pseudo-PARPtransposon silencing (RDTS) domain. In summary, we show an unexpected functionallink between these critical transposon silencing pathways. Overall design: To investigate the conservation of the DUF3715 domain between TEX15 and TASOR we established Tasor-deficient mouse ES cell lines which were subsequently reconstituted with mutant and chimeric TASOR constructs.