Understanding the molecular mechanisms by which large, multi-subunit complexes engage in DNA-centric processes using cryo-electron microscopy (cryo-EM) and other biophysical and biochemical approaches. We focus on two main topics: (1) how eukaryotic gene transcription is regulated at different stages, and (2) how various types of DNA damage are repaired and why deficiencies in these repair pathways lead to pathology of cancer predisposition or accelerated aging.