Evolutionary analysis of THAP9 transposase: conserved regions, novel motifs

Abstract

THAP9 is a transposable element-derived gene that encodes the THAP9 protein. It is a homolog of Drosophila P-element transposase (DmTNP). hTHAP9 belongs to the THAP (Thanatos-associated protein) protein family in humans, which has twelve proteins (hTHAP0-hTHAP11). Human THAP proteins have a ~90 amino acid long conserved THAP domain located at the N-terminal end of the protein. The THAP domain is a C2CH type Zinc Finger domain that binds specific DNA sequences and has a conserved secondary structure, namely a characteristic β-α-β fold. THAP family proteins are known to be involved in various human diseases like torsional dystonia, hemophilia, heart diseases, and multiple cancers. Also, the THAP9-AS1 gene, which is the neighboring gene in the 5' upstream region of THAP9, is overexpressed in pancreatic cancer. But the exact functional role of THAP9 and its association with various diseases remains a significant gap in our understanding. Here, we present the evolutionary analysis and extensive in silico characterization, including predicting domains and putative post-translational modification sites for THAP9 to understand its function better. Our studies identified some previously unreported functional features in the THAP9 protein sequence, including four adjacent motifs following the THAP domain: N-glycosylation site, Protein kinase C (PKC) phosphorylation site, Leucine zipper domain, and Bipartite nuclear localization signal (NLS). These motifs, which are highly conserved in mammals, may play a role in the subcellular localization of THAP9. The study also revealed two N-myristoylation sites within the THAP domain, pointing towards the post-translational modification of THAP9. We also observed that the THAP9 has evolved under a strong pervasive purifying selection, yielding high conservation of THAP9. Furthermore, investigation of THAP9 expression profiles in various cancer and matched normal datasets demonstrated overexpression and underexpression in Testicular cancers and Thymic Epithelial Tumors respectively. These findings make Testicular cancer and Thymic Epithelial Tumor good candidates for further examination on the role of THAP9 in cancer.

Pan-Cancer Analysis Reveals the Prognostic Potential of the THAP9/THAP9-AS1 Sense–Antisense Gene Pair in Human Cancers

“…It has been reported that THAP9 is a highly conserved gene, which has been identified in 178 organisms [ 106 ]. The human THAP9 gene has 6 isoforms, out of which only one is known to encode for aprotein that is homologous to the Drosophila P-element transposase.…”