S-SETMAR in the biogenesis of glioblastoma : a protective role ?

Born 45 million years ago, SETMAR is a fusion gene only present in higher primates. It is made of three exons, the two first given by the SET gene and coding for methyltransferase functions, the third given by the Hsmar1 transposase gene and coding for recombinase functions. The full length SETMAR protein (FL-SETMAR) is described as a genome keeper, expressed in main tissues, but with different levels. In cancer cells, the SETMAR gene is over-expressed, and FL-SETMAR sustains oncogenic processes, probably through its involvement in DNA repair by Non-Homologous End-Joining (NHEJ), replication stress response and chromosome decatenation. Under certain circumstances, SETMAR pre-mRNA undergoes alternative splicing, leading to the production of shorter proteins, enriched in cancer stem cells. One of them, S-SETMAR, was first discovered in glioblastoma (GB), and more recently in colorectal cancers. S-SETMAR lacks a part of the pre-SET domain and the whole SET domain, both encoded by exon 2. As a result, S-SETMAR is unable to methylate proteins, as does FL-SETMAR with a moderate efficiency. Little is known about the role of S-SETMAR. It has been recently shown that S-SETMAR, when enriched in tissues surrounding GB, correlates with an increased patient’s survival. In order to understand how S-SETMAR can have a protective role in glioblastoma biogenesis, the transcriptomes of established glioblastoma cell line expressing or not S-SETMAR were compared. This allowed the identification of deregulate pathways.