Life Sciences & Biotechnology
Title : | Regulation of eukaryotic mobile genetic elements |
Area of research : | Life Sciences & Biotechnology |
Principal Investigator : | Dr. Sharmistha Majumdar, Indian Institute Of Technology (IIT) Gandhinagar, Gujarat |
Timeline Start Year : | 2022 |
Timeline End Year : | 2025 |
Contact info : | sharmistham@iitgn.ac.in |
Details
Executive Summary : | The human genome contains ~ 50 genes that were derived from transposable elements and many are now integral components of cellular gene expression programs. Our research focuses on the newly discovered vertebrate homologs (THAP9) of the Drosophila P element transposase (TNP). The TNP protein is involved in the cleavage and subsequent integration of the P-element DNA transposon (Kaufman, 1992). P-elements are a family of DNA-based transposons in Drosophila melanogaster that move about the fruit fly genome, cause hybrid dysgenesis and have been used extensively as tools for Drosophila genetics and genomics. The discovery of the human THAP9 gene suggests a possible invasion of P element-like transposons into vertebrates. We have made the surprising discovery that human THAP9 can mobilize Drosophila P- transposable elements across species (Majumdar 2013). Our results indicate that human THAP9 is an active DNA transposase that, although domesticated, still retains the catalytic activity to mobilize transposons. This is the first report, beyond the V(D)J recombination system, of an active DNA transposase in the human genome. Our biochemical analysis has also demonstrated that much like its Drosophila homolog, human THAP9 can oligomerise via a conserved coiled coil domain (Majumdar 2021a) and catalyse DNA cleavage via a conserved RNaseH-like domain (Majumdar 2021b). The exact cellular function and physiological role of human THAP9 is however still unknown. Preliminary results suggest that THAP9 is preferentially expressed in the mitochondria and overexpressed in certain cancers (Majumdar et al unpublished data, Lohmann 2012, Jia 2019, Li 2019, Jiang 2019). The proposed study aims to understand how THAP9 is regulated. We hypothesise that THAP9, which can transpose DNA in the fruit fly embryo, may have evolved by a possible loss or modification of this transposition function in higher vertebrates. In this study, we would like to investigate the regulatory roles of stress as well as THAP9-interacting partners like GTP, lncRNAs and other proteins. These studies will help us understand the significance of transposon-derived genes in the human genome which can be exploited as powerful tools for genome engineering and gene therapy. Moreover, we hope to unravel the correlation between THAP9 (and its isoforms) and disease. |
Total Budget (INR): | 59,98,696 |
Organizations involved