DDB_G0276451 - dictyBase/community-annotations GitHub Wiki

DDB_G0276451 has only one recognizable blast hit outside the Amebozoans; this is to the proapoptotic protein SIVA. The homology is weak, but when vertebrate SIVA is blasted back to Dicty, DDB_G0276451 is the only hit. The homology is confined to an array of conserved cysteine residues, which are found in the C-terminus of both vertebrate SIVA and Dicty DDB_G0276451. These are considered to bind zinc Nestler_ et al_, Molecular and Cellular Biochemistry 287(2006) but the exact role of the resulting zinc finger(s) is not clear. The "death domain" found at the N-terminus of the human protein is not conserved in DDB_G0276451.

SIVA is a suspected transcriptional target of E2F1 Fortin et al, Journal of Biological Chemistry 279 (2004). E2F1 is well known to be bound and inactivated by the retinoblastoma protein. Interestingly, DDB_G0276451 is more than tenfold overexpressed in a Dicty strain lacking the Dicty retinoblastoma homologue. This suggests that DDB_G0276451 is also a direct or indirect E2F target in Dicty. The promoter contains the 8-mer CCCGCCAA, which is roughly 20-fold enriched in the promoters of rblA-repressed genes. In Dicty multicellular development, DDB_G0276451 shows an expression trajectory (see DictyExpress) which is highly typical of rblA-repressed, putative cell-cycle regulated genes (MacWilliams, personal observation).

The role of SIVA in the cell cycle is obscure. In vertebrates, SIVA is induced by p53, and induces apoptosis by at least two different pathways (SIVA is named after the Hindu god of destruction). If anything, it seems likely to be a negative regulator of proliferation. Most Rb targets in Dicty have positive roles in cell cycle progression, but Dicty rblA itself, which is clearly a negative proliferation regulator, is one of the most strongly rblA-repressed genes (repression factor 27). Other negative cell-cycle regulators repressed by rblA are DDB_G0276451 and DDB_G0291842, putative orthologues of the wee kinase (repression factors greater than 6), and the spindle checkpoint components bub1, bub3, and mad2 (repression factors between 4 and 6).

It thus seems plausible that DDB_G0276451 is a cell-cycle regulated, antiproliferative protein in Dicty, the zinc-binding motif of which has been conserved in evolution, and which, after the invention of apoptosis in early metazoans, was incorporated into an apoptotic regulator. It is conceivable that the original antiproliferative function is also conserved in metazoans. It would be interesting to know what this function is.

Harry MacWilliams, May 2010

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