The main research focus of my lab is the relationship between nuclear structure and nuclear function. Altered nuclear shape is observed in certain types of disease, such as cancer and during aging. However, the relationship between changes to nuclear morphology and either disease state or aging is unknown. Moreover, in many cell types, there is a constant ratio between nuclear volume and cell volume. How this ratio is established and its importance to normal cell function is unknown. Finally, there are many basic questions related to nuclear structure and function that remain to be answered. For example, how does the nuclear envelope form at the end of mitosis? What dictates the formation of a single nucleus that encompasses all chromosomes rather than multiple nuclei that contain a subset of chromosomes? How does the nuclear envelope expand? Since the nuclear envelope is continuous with the endoplasmic reticulum (ER), what role does the ER play in nuclear morphology? How does the nuclear envelope contribute to the intra-nuclear organization of chromosome domains and how does nuclear morphology affect processes such as DNA replication, transcription, splicing, and repair of DNA damage? Given the link between pathology and nuclear morphology, we expect that gaining insight into the proteins and processes that affect nuclear shape will lead to a better understanding of disease progression, diagnostics, prevention, and treatment.
In order to uncover proteins and processes that contribute to nuclear structure and integrity, we are conducting genetic screens in budding yeast and C. elegans for mutations or conditions that alter nuclear shape. For example, we found that lipid biosynthesis plays an important role in maintaining nuclear shape in both yeast and in C. elegans (see Campbell et al. and Golden et al.). Based on our studies, we proposed a model that links ER structure to nuclear shape (see Webster et al. and Webster et al.). We also discovered that in yeast cells, which undergo closed mitosis (i.e., without nuclear envelope breakdown), a mitotic delay results in altered nuclear shape in a specific region of the nuclear envelope (see Witkin et al.). This observation raises the possibility that at least in yeast, the nuclear envelope is not homogenous; rather, it has distinct domains that are capable of expanding. Studies are underway to determine how the yeast nuclear envelope expands, what defines these nuclear envelope domains, and how various mutants that alter nuclear shape contribute to nuclear morphology and nuclear function.
We also conducted a systematic RNA interference screen in C. elegans to identify additional genes and pathways that contribute to nuclear shape and function. We currently have a large number of genes that, when down-regulated, affect nuclear structure and these fall into various functional categories—some of which are quite surprising, such as RNA processing, ribosome biogenesis, and protein transport (see Joseph-Struss et al.). We are currently investigating the mechanisms by which these genes affect nuclear organization and nuclear function.
The main research focus of my lab is the relationship between nuclear structure and nuclear function. Altered nuclear shape is observed in certain types of diseases, such as cancer and during aging. However, the relationship between changes to nuclear morphology and either disease state or aging is unknown. We use budding yeast and C. elegans, two very powerful genetic systems, to identify genes that, when mutated, lead to abnormal nuclear shape.
We currently are looking at a large number of genes that affect nuclear structure, and these fall into many functional categories, some of which are quite surprising, such as RNA processing, ribosome biogenesis, and protein transport. The next step is to understand how these genes affect nuclear shape and to determine whether nuclear processes, such as transcription, DNA replication, and DNA repair, are affected by the alteration to nuclear shape.