Department of Biology - Primary Appointment
Department of Genetics - Joint Appointment
Director of the Curriculum in Molecular Biology and Genetics
Key words: Genetics of cell cycle control; Regulation of Gene Expression; Drosophila development
Our research focuses on understanding the molecular mechanisms that regulate DNA replication and cell proliferation during animal development. We study how cells make the decision to proliferate or not. The breakdown of the control of this decision is one of the events that contribute to the generation of cancer. We study this problem using the fruit fly Drosophila melanogaster because the genes controlling cell proliferation in humans and fruit flies function in essentially the same way. This allows us to exploit certain advantages that Drosophila has as a research tool, including the ease with which genetics (making and analyzing mutants) and cell biology (using microscopy to observe cell proliferation) can be applied to the study of gene function in the context of a whole animal. Some of the genes that we study constitute a regulatory mechanism (the “RB/E2F” pathway) that is defective in virtually all cancers. The hope is that understanding how these genes function in normal Drosophila development will give us clues to how they might malfunction in the deregulated growth typical of cancer.
Cell proliferation is controlled by an orderly process of events called the cell cycle, which for most cells consists of four phases: G1-S-G2-M. The DNA of chromosomes is replicated during the “S” or synthesis phase and duplicated chromosomes are segregated to daughter cells during the “M” or mitotic phase when cell division occurs. G1 and G2 are “gap” phases during which the regulation of entry into S phase and M phase occurs.
Current Research Projects
Our current research projects focus on how gene expression is controlled during the cell cycle, with a particular emphasis on the G1-S transition.
PROJECT I: Mechanisms of E2F function and regulation by ubiquitin-mediated proteolysis
Determining the mechanisms of normal cell cycle control is critical for our understanding of both development and oncogenesis. During development, cell proliferation occurs by coordinating progress through the cell cycle with growth. Conversely, cell cycle arrest occurs prior to, and is often necessary for, terminal differentiation. Cell proliferation and cell cycle arrest are also highly regulated after the completion of development: stem cells in adult tissues are under tight cell cycle control, as are quiescent cells that only proliferate in response to particular stimuli. Breakdowns in cell cycle control in any of these circumstances can have drastic consequences and contribute to the deregulated growth typical of cancer. This project focuses on gene expression mechanisms that control the G1-S transition because this is when most cells decide whether to enter or to exit the cell cycle. The goals of the project are to determine how transcription factors (the pRb tumor suppressor and E2F) and protein ubiquitylation/proteolysis (cullin dependent ubiquitin ligases) regulate the entry into S phase during Drosophila development.
PROJECT II: Mechanisms of Replication-Associated Histone mRNA Biosynthesis
Proper gene expression is critical to all aspects of cell and developmental biology and involves the compartmentalization within specific nuclear domains of factors needed for production of mature mRNA. This is particularly true for cell cycle-regulated synthesis of histone mRNA, which is necessary for chromosome duplication and transmission in proliferating cells. The histone locus body (HLB) is a newly described nuclear body that associates with replication-dependent histone gene clusters and contains factors necessary for histone mRNA biosynthesis. These include transcription and pre-mRNA processing factors like U7 snRNP, which interacts with the 3’ end of nascent histone transcripts and stimulates accurate pre-mRNA processing and release of a unique mRNA that is not polyadenylated. This project will determine the molecular mechanisms of HLB formation and cell cycle regulation, and how this contributes to histone mRNA biosynthesis during Drosophiladevelopment. Our goal is to provide new insight into how specific aspects of nuclear architecture contribute to gene expression events necessary for cell proliferation.