Identification of a Novel p53 Regulated Endogenous Retrovirus MMERGLN

Advisers: Robyn Leary and Professor Anindya BagchiWith roughly half of all tumors with mutations in the TP53 gene, TP53 undoubtedly is a tumor suppressor gene that plays a critical role in the prevention of cancer. TP53 responds to cellular stress in cells, either metabolic disorder or genetic damage for example, and becomes transcriptionally activated to produce the p53 protein. Several genes that are directly targeted by p53 have been studied extensively and their role in cellular apoptosis and senescence are well documented. However, whether p53 can also regulate expression of repetitive elements that comprise a significant part of the genome, and their possible consequence, is not known. The mouse genome, in addition to known genes, also has several endogenous retroviruses, short DNA sequences derived from ancient viral infections that are now part of the genome. In my thesis work, I characterize one specific endogenous retrovirus, MMERGLN, and explore MMERGLN’s relationship with the p53 protein. Not only does MMERGLN show p53 regulation according to RNA Sequence data, MMERGLN also possesses p53-binding sites. Here we have identified MMERGLN transcripts that are present in a p53-dependent manner and MMERGLN is expressed body-wide in mouse. Furthermore, we demonstrate that multiple copies of MMERGLN contain all the components necessary for retrotranspostion or infection suggesting this genomic element may still be active. In order to determine a potential function for this genomic element, we investigated the ability of MMERGLN to act as an enhancer by identifying genes with differential transcription near MMERGLN insertion sites in p53 wild type and p53 null mice. Finally, with the purpose of understanding how MMERGLN is prevented from spreading throughout the genome, we investigated the mechanism by which MMERGLN is restricted, and see evidence for cytosine deamination mediated by the Apobec proteins. Our results demonstrate a paradigm shift in how transposable elements are regulated by p53 and suggest a new role for MMERGLN in tumor suppression. We anticipate these studies to shed light on the potential role of transposable elements in preventing disease.This research was supported by the Undergraduate Research Opportunities Program (UROP)