Abstract: Faithful duplication of the genome is crucial for proper cell division and thus the genetic integrity of all organisms. Errors in DNA replication can lead to genomic instability, a characteristic feature of most cancer cells. A key component of the replication machinery (replisome) is the DNA helicase, which separates the double helix into its component strands so they can be copied. In this talk, I will first discuss our efforts to decipher the molecular mechanism of the Cdc45/MCM2-7/GINS (CMG) complex that acts as the replicative helicase in eukaryotes, The basic mechanism by which this helicase unwinds DNA at the replication fork has been controversial. CMG was proposed to function as a physically coupled pair of helicases that pumps double-stranded DNA through the helicase central channel, splitting the duplex apart when it emerges from the protein complex. Others challenged this view and proposed that they function as single hexamers that encircle and translocate along a single strand and unwind DNA by excluding the other strand from the central channel (“steric exclusion”). Determining which model is correct has profound implications for the spatial organization and inner workings of the replisome. To better understand how CMG interacts with DNA, we developed novel methodologies that combine single-molecule imaging and DNA nanomanipulation in extract-based systems. I will also present a new single molecule tool that we developed to perform fluorescence super resolution imaging of DNA replication intermediates.

Biography: Hasan Yardimci obtained a BSc degree in physics from Bogazici University, Turkey, in 1999. He then joined the graduate program of Johns Hopkins University and received his PhD in soft condensed matter physics in 2006. As a postdoctoral research fellow at University of Illinois at Urbana-Champaign (2006-2008), Hasan studied the molecular mechanism of a mitotic kinesin using single molecule imaging methods. He then moved to Harvard Medical School (2008-2013) as a postdoc, where he focused on single molecule studies of eukaryotic DNA replication. In 2013, Hasan established his own research group at Clare Hall Laboratories, Cancer Research UK London Research Institute (now part of the Francis Crick Institute). His laboratory develops and applies novel single molecule tools to study DNA replication and repair.