Karl Lohmann Prize:
Structural biology of nucleosome passage
Eukaryotic genomes are organized in a structure called chromatin. Chromatin is a protein-nucleic acid complex and its most fundamental unit is the nucleosome. Whereas nucleosomes allow compaction of the genome into the tight confinements of the nucleus, they also represent a significant challenge to nucleic acid transacting machines. I examine the issue of chromatin accessibility in the context of chromatin remodeling where molecular machines, termed chromatin remodellers, allow repositioning of nucleosomes to influence cell fate. An integrated structural biology approach utilizing solution biochemistry, cryo-EM and X-ray crystallography allowed me to show how the S. cerevisiae chromatin remodeler Chd1 engages a mononucleosome and how its activity is regulated, and how the H. sapiens remodeler CHD4 is impacted by cancer and other rare disease related mutations. In a related study, I was able to obtain the structure of a transcribing RNA polymerase II-nucleosome complex to provide a model for understanding chromatin in the context of transcription and gene regulation.