Assistant Professor, Genetics - GIDP
Dr. Bolger's research focuses on understanding post-transcriptional gene regulation and its relation to human disease, especially cancer. They are interested in how the dynamics of mRNA-protein complexes are controlled, focusing on a set of RNA helicase and RNP remodeling enzymes termed the DEAD-box proteins. DEAD-box proteins are required at virtually every step of gene expression to promote appropriate RNA-RNA and RNA-protein interactions, and several of them have been linked to cancer and other diseases. In particular, mutations in a DEAD-box protein, Ded1 in budding yeast and DDX3 in humans, have been strongly linked to medulloblastoma, the most common pediatric brain cancer. The function and regulation mechanisms of Ded1/DDX3, as well as the effect of the identified mutations, are under intense study in his laboratory. Uncovering these mechanisms and expanding this research to other studies of mRNP dynamics will both promote our basic understanding of the regulation of gene expression and elucidate the molecular pathways that influence cancer and other diseases.
During Dr. Bolger's research career, he has gained broad experience in the basic research of gene expression regulation as well as in cancer biology. As a graduate student in Molecular Cancer Biology, he gained a strong background in cancer biology. Further, during multiple levels of his training, he studied different aspects of gene expression, including transcription regulation, nucleocytoplasmic trafficking, and translation.
As a postdoctoral fellow, Dr. Bolger initiated a project to examine functional coupling between mRNA nuclear export and protein translation. He has continued and expanded his postdoctoral work in his own laboratory, using genetic, biochemical, and cell biology techniques to address fundamental biological questions and understand the relationship between normal function and disease.
Dr. Bolger joined the University of Arizona Cancer Center in an effort to further expand the cancer aspect of his research, and he has found input from Cancer Center members (e.g. during “works-in-progress” meetings) to be very helpful in formulating future research directions. Furthermore, Dr. Bolger plans to expand some of their current research into animal models within the next three to five years as a collaborative effort, and the Cancer Center will be a valuable resource in pursuing this collaboration.
Eukaryotic gene expression is a fundamental cellular activity that is critical for cellular identity, function, and physiology. During gene expression, a messenger RNA (mRNA) is generated by transcription and undergoes a number of different steps, including splicing and nuclear processing, nucleocytoplasmic export and localization, translation, and decay. These steps result in dynamic changes to the RNA sequence, structure, and the cohort of proteins bound to the mRNA. Furthermore, these changes need to occur with the proper timing and in the correct sequence to avoid aberrant expression. Therefore elaborate regulation of mRNP dynamics is required for proper gene expression.
At virtually every step in gene expression, members of a highly conserved protein family called the DEAD-box proteins are required for facilitating mRNP transitions by acting either as RNA helicases or as ribonucleoprotein (RNP) remodeling enzymes. Furthermore, by regulating their activity, the potential exists to control mRNAs in different subsets and in response to different conditions. Thus we hypothesize that the DEAD-box proteins exert overarching control of mRNP dynamics in gene expression.
GLE1 is an essential gene required for mRNA export in eukaryotes from yeast to humans, and in this role it stimulates the activity of the DEAD-box protein Dbp5 in conjunction with a small molecule, inositol hexakisphosphate (IP6). In addition, mutations in human GLE1 cause a developmental motorneuron disorder called lethal congenital contracture syndrome-1 (LCCS1). Recently we have discovered previously uncharacterized functions of Gle1 in both initiation and termination of translation. Furthermore, we have shown that Gle1 regulates the activity of a different DEAD-box protein, Ded1, in translation initiation. Thus we have found that Gle1 is a multi-functional regulator of DEAD-box proteins, and we propose that in doing so it acts to coordinate different steps of gene expression.
The DEAD-box protein Ded1 has long been known to function in translation regulation; however, its molecular mechanism remains unclear, as does its regulation. On the other hand, its human ortholog, DDX3, has increasingly been linked to disease. Alteration of DDX3 has been observed in several cancers, including a high mutation rate in the brain cancer, medulloblastoma. DDX3 also has roles in the replication of several viruses, including HIV and hepatitis B and C.
Our research in the Bolger lab has dual goals: 1. addressing fundamental biological questions, and 2. utilizing this knowledge to advance human health. The Bolger laboratory uses the budding yeast Saccharomyces cerevisiae as a model system, and takes advantage of the combination of genetics, biochemistry, and cell biology allowed by yeast work. Our long-term goal in fundamental biology is to uncover the regulation of mRNP dynamics. Specifically, we are focusing on the in vivo roles, molecular targets, and regulation of DEAD-box proteins. Presently, we are examining the regulation of Ded1 in translation, both by Gle1 and by post-translational modifications. We are also interested in examining the function and regulation of other DEAD-box proteins. Our research will not only greatly increase our understanding of how these factors function in translation but will elucidate potential mechanisms for control of gene expression, including aiding future studies of functional coupling between mRNA export and translation.
In these studies, we seek to understand the normal functioning of these factors. Given that the cellular functions of Ded1/DDX3 and Gle1 are not well-characterized, understanding of their physiological functions is critical to examining their roles in cancer and other diseases. Furthermore, we have begun a project to characterize the role(s) of DDX3/Ded1 in medulloblastoma, which has the potential to directly impact the understanding of this cancer. Our work may thus open up new avenues for therapies, either for cancer or for the other pathologies related to this research.