Grant: Project Grant

Atomic level descriptions of the molecules of life are mostly focused on static pictures, neglecting the fact that these molecules are dynamic and that their motions play critical roles in function. One example where this is the case is chromatin, consisting of DNA and proteins called histones, which packages nearly 2 meters of DNA into a compact structure that allows it to fit inside the nuclei of cells. This DNA must be accessible to a host of cellular machines to ensure the fidelity of our genome, which in turn requires a high degree of flexibility. Although static pictures of the fundamental unit of chromatin - the nucleosome core particle (NCP) - have been elucidated, there are few investigations into how the NCP changes its shape over time in response to biological stimuli or to cancer mutations. Using a technique called solution Nuclear Magnetic Resonance spectroscopy that my laboratory has helped to pioneer for studies of biological molecules, we will elucidate how the motions of the NCP are changed from modifications that control processes such as DNA repair or replication of the genetic code, via mutations that result in cancer, and through binding of protein factors. These changes in motion will then be correlated with changes in function to establish a structure-dynamics-function paradigm for NCPs. The over-arching goal is to elucidate how the dynamics of the histone components of NCPs enable function, thereby significantly extending our picture of NCPs from static molecular complexes to the dynamic structures that they are and helping to pave the way for treatments for diseases that arise from changes in histone dynamics.