Search

Simple Summary: The origin recognition complex (ORC) selects sites for replication initiation by recruiting a pair of hexameric minichromosome maintenance (MCM) complexes to replication origins where the pre-replication complex (Pre-RC) is assembled, and the bidirectional replisomes are formed. In yeast, site selection by ORC is largely based on sequence-specific binding and Pre-RCs are established where ORC binds. In humans, site selection by ORC is largely based on chromatin landscapes and Pre-RCs are formed far away from ORC binding sites. This review compares these two very different modes of origin selection that can be traced to a small variation in the structures of subunit 4 of the yeast and human ORC. Understanding human DNA replication through the study of yeast has been an extremely fruitful journey. The minichromosome maintenance (MCM) 2–7 genes that encode the catalytic core of the eukaryotic replisome were initially identified through forward yeast genetics. The origin recognition complexes (ORC) that load the MCM hexamers at replication origins were purified from yeast extracts. We have reached an age where high-resolution cryoEM structures of yeast and human replication complexes can be compared side-by-side. Their similarities and differences are converging as alternative strategies that may deviate in detail but are shared by both species. [ABSTRACT FROM AUTHOR]

I had my eyes set on DNA replication research when I took my first molecular biology course in graduate school. My election to the National Academy of Sciences came just when I was retiring from active research. It gives me an opportunity to reflect on my personal journey in eukaryotic DNA replication research, which started as a thought experiment and culminated in witnessing the determination of the cryoelectron microscopic structure of the yeast replisome in the act of transferring histone-encoded epigenetic information at the replication fork. I would like to dedicate this inaugural article to my talented trainees and valuable collaborators in gratitude for the joy they gave me in this journey. I also want to thank my mentors who instilled in me the purpose of science. I hope junior scientists will not be disheartened by the marathon nature of research, but mindful enough to integrate and pause for other equally fun and meaningful activities of life into the marathon., Competing Interests: Competing interests statement:The author declares no competing interest.