Retroviruses are ubiquitous agents that cause cancer in humans and animals. For the retrovirus mouse mammary tumor virus (MMTV), cancer arises when the viral genetic material becomes integrated into the host chromosome and activates the expression of cellular proto-oncogenes. Although discovered in the 1930s, the mechanisms used by retroviruses like MMTV to replicate their genomes and the strategies used by cells to defend against retrovirus infection are not well understood. In addition to the threat of exogenous retroviruses, endogenous retro-transcribing elements, like the LINE-1 retrotransposon, actively replicate in cells and contribute to cancer by dysregulating the expression of cellular genes that control cell growth, by causing DNA double-stranded breaks, and by inducing genomic instability. Our preliminary data suggest that MMTV may interact with the same group of host factors in the cytoplasm as reported for the LINE-1 retrotransposon, raising the intriguing possibility that a common cellular pathway has evolved to defend against multiple types of retro-transcribing elements. In the case of MMTV, viral capsids are formed at discrete sites in the cytoplasm that associate with host mRNA processing factors Yb1, Mov10, and Ago2. We envision that the MMTV RNA might be trafficking to these sites to avoid translation machinery, instead being packaged into assembling virus capsids. However, for LINE-1, these same host factors appear to play a central role in host defensive efforts to degrade LINE-1 RNA and limit retrotransposition. Together, these observations led to the hypothesis that cytoplasmic sites of mRNA processing represent the battleground between MMTV and LINE-1- encoded factors trying to promote their own replication and host factors trying to restrict replication. We will test this hypothesis through two specific aims. First, focusing on the oncogenic retrovirus MMTV, we will examine the effect of altered expression levels of cellular mRNA processing factors on viral capsid assembly, virus production, and virus infectivity. Our goal is to determine whether mRNA processing factors promote steps in virus replication or interfere with MMTV assembly and infectivity. Regardless of the outcome, these experiments will be informative and lead to a deeper understanding of MMTV biology. Second, we will determine whether a common cellular pathway acts on MMTV and LINE-1 retroelements by examining the localization of MMTV capsids and LINE-1 encoded ribonucleoprotein complexes in the same cells. Finally, features of MMTV and LINE-1 elements that control their subcellular trafficking will be identified using a domain-swapping gain-of-function approach. These experimental results will provide novel insights into retroelement-host interactions that contribute to the development of cancer. In the future, we may find that these results are broadly applicable if these host interactions are shared by other retro-transcribing elements. Ultimately, this research may provide new targets for the prevention or treatment of cancers caused by retroviruses and retrotransposons.
Retroviruses and retrotransposons replicate through an RNA intermediate and integrate into the host genome, causing mutations that lead to cancer by disrupting cellular gene expression or damaging DNA. Little is known about the host cell defensive mechanisms that aim to fight against these genome invasions; however, evidence suggests that host cell machinery may be hijacked by retroviruses and retrotransposons to complete their replication cycles. This proposal seeks to understand the role of cellular defensive factors in retrovirus and retrotransposon replication with the ultimate goal of preventing or treating retrovirus-induced cancers.!
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