Transcription factor–DNA recognition mechanism

It is now well established that proteins use both the one-dimensional (1D) sequence and the three-dimensional (3D) shape of DNA to bind to and act on their target sites. However, our current mechanistic understanding of protein-DNA recognition lags behind the growing realization of their biological importance, and fundamental components of the recognition code remain poorly understood. For example, although many proteins distort the DNA, we still do not know the energetic costs of these distortions for most protein-DNA binding reactions. Furthermore, for most reactions, we do not even know the energetic contributions of individual bases within different base pairs or the contributions of the DNA sugar-phosphate backbone.

We seek to fill in these gaps in our knowledge by deeply characterizing how changes in the DNA structure, the DNA bases, and the DNA backbone affect protein-DNA interactions.

Biophysical principles of mutagenesis

Mutations drive evolution, account for genetic variants in the population, and are the primary cause of cancer and other genetic disorders.

The lack of a deep molecular understanding of the biochemical processes that generate mutations (e.g., DNA lesion recognition) limits our ability to better understand and ultimately treat and prevent genetic diseases.

In our lab, we study and characterize in an unprecedented scope, the biophysical principles behind these process. 


The impact of structure on DNA biochemistry

Genomic DNA consistently undergoes structural changes that are imposed by the cellular DNA packaging, and by fundamental processes such as replication, DNA repair, and transcription. Similar deformations have been seen in vitro in many protein-DNA complexes, including those of TFs and repair enzymes. However, the effect of these structural changes on DNA binding affinities was measured only for a limited number of proteins with a limited number of DNA sequences. Therefore, we currently do not understand nor can we predict the impact of such changes on DNA biochemistry in the genome.

We are developing and using novel high-throughput assays to study and characterize the impact of these genomic forces on the fundamental interactions between protein and DNA within the cell.