The faithful transmission of the genetic information encoded in chromosomal DNA is essential for cellular life and requires the accurate duplication of genomes through DNA replication prior to cell division. In eukaryotes, genomic DNA is packaged with histones and further condensed into higher-order chromatin structures, which ultimately allows 2 meters of DNA to be fit into the tiny nuclei of human cells. This compaction of DNA, however, also poses a challenge to many DNA-transacting machines, including the DNA replication machinery, by preventing access to the DNA helix. Alterations in the chromatin landscape thus provide a powerful means to temporally and spatially regulate DNA-dependent processes; nonetheless, we are only beginning to understand the molecular mechanisms that underpin these regulatory events, particularly in the case of DNA replication.
How are changes in chromatin architecture coupled to DNA-associated processes such as DNA replication?
How do nucleosomes and other factors guide proteins and their assemblies to chromosomal loci? How do they influence their activities?
How do different DNA replication events in turn alter the local chromatin environment.
Our research is focused on answering these fundamental questions using an integrated mix of biochemical, biophysical and structural methods (single-particle cryo-electron microscopy and X-ray crystallography) to identify and visualize key chromatin-associated replication intermediates at atomic or near-atomic resolution. In combination with in vivo genetic approaches, our efforts will help establish molecular models for the complex interplay between chromatin structure and DNA-associated processes, with relevance to both health and disease.