The molecular basis of chromosome organization and its impact on growth, development and disease
In cells the DNA is organized by proteins into a structure known as chromatin. The first level of chromatin organization is mediated by histones. Both the nature of higher-order chromatin organization and the proteins involved in the process are mostly unknown. Yet, this organization is important for both genome functionality and integrity. Cohesin is a member of a conserved family of protein complexes called Structural Maintenance of Chromosomes (SMC). Cohesin and other SMCs are involved in a broad spectrum of functions that include chromatin organization, transcription regulation, cell differentiation, and maintenance of genome integrity. Furthermore, aneuploidy, cancer and developmental syndromes are associated with malfunction of SMC proteins, indicating their medical importance. The term cohesinopathy collectively describes a growing number of cohesin-associated diseases, although the molecular basis of these disorders is elusive.
The complex architecture of cohesin and the complicated features of its in vivo activity have impeded attempts to elucidate its molecular functions. To overcome these difficulties we developed a holistic approach utilizing biochemistry, genetics and molecular biology to study the molecular mechanism of cohesin in the yeast Saccharomyces cerevisiae. In addition, we are interested in understanding how malfunction of cohesin is affecting development and tumorgenesis.
The wide range of cohesin activities in the cell requires a dynamic regulation. A differential array of modifications and auxiliary factors regulate cohesin activity. However, neither the characterization of these regulators is complete nor their effect on cohesin activity is well understood. We study how cohesin is regulated throughout the cell cycle and in response to environmental and cellular stimuli such as DNA damage. We use a genome-wide approach to gain a detailed map of cohesin’s modifications and interactions with auxiliary factors. Moreover, we believe that mutations that impair cohesin regulation play a part in cohesinopathy. Our long term goal is to search for such mutations in cancer-derived cell lines and other clinical relevant syndromes and to study their contribution the pathology.
Our current knowledge of the processes shaping the chromosome is incomplete. Dissecting the activity and regulation of cohesin on the molecular level will provide new insight into fundamental processes in the cell. Furthermore, it may be used for developing new therapeutic approaches to cancer and other human disorders.