University College London, United Kingdom
Complex programmes of transcription define cellular identity and function and are established by combinations of activators and coactivators. Coactivators catalyse chromatin modifications and recruit the transcriptional machinery to stimulate gene expression, but they lack DNA specificity and must interact with sequence-specific activators when targeting specific genes. The chromatin modifying coactivators SAGA and NuA4 associate with activators via the Tra1 subunit that is common to both complexes. In addition to transcription regulation, they also have additional roles in DNA repair and RNA transport. However, their size and complexity have limited our understanding of their mechanisms and functions.
We will investigate the molecular mechanisms of Tra1 by examining its interactions with activators and determining the effect on recruitment of SAGA/NuA4 and subsequent mRNA production. This will be integrated with our cryo-EM studies of the complete NuA4 complex.
Our findings will provide an integrated understanding of this multifunctional macromolecular machine.