Mechanisms of gene transcription and DNA replication in eukaryotic cells
Gene transcription allows cells to decipher the information encoded in the DNA to initiate production of proteins. Accurate DNA replication is necessary to safeguard DNA and the information it contains. Perturbations in regulation of transcription and DNA replication are a common cause of human diseases, including cancer. DNA replication errors lead to genome rearrangements and mutations that can result in dysregulated transcription. Using their pathologic transcriptional programs cancer cells can grow and proliferate outside of the natural limits. At the same time, they often become over-dependent on specific proteins or regulatory pathways which creates opportunities for development of targeted therapies once we understand the underlying mechanisms.
In all eukaryotic organisms, from simple unicellular yeast to humans, DNA is stored as chromatin, which consists of a DNA strand wrapped around bead-like structures made of histone proteins. The histone octamer and a section of a DNA strand associated with it are called a nucleosome. Cells carefully regulate nucleosome positioning because nucleosomes can restrict the access of proteins to DNA. Further, many proteins involved in transcription, DNA replication, and other cellular processes can ‘read’ specific modifications on histone proteins which are dynamically deposited and erased by other specialized factors.
Our lab studies complex mechanisms regulating transcription and DNA replication in a dynamic chromatin environment. We are especially interested in early stages of both processes when respective machineries are assembled and activated. We currently focus on chromatin readers from the BET family, which ‘read’ acetylation marks on histones and other proteins to regulate transcription. Our recent findings have also implicated BET proteins in DNA replication. Importantly, BET factors were recognized as attractive drug targets for many types of cancer, but their regulation and roles are poorly understood, which limits drug discovery efforts. We primarily use yeast as an experimental system because the mechanisms we investigate are conserved and the yeast model offers unparalleled flexibility in experimental design.