Previous Seminars
ICaMB Seminar - Duncan Smith
- Venue: Baddiley Clark Seminar Room
- Start: Wed, 24 Jan 2018 13:00:00 GMT
- End: Wed, 24 Jan 2018 14:00:00 GMT
Prior to each division, eukaryotic cells must replicate their entire genome accurately and in a timely fashion. DNA replication is mediated by hundreds to thousands of replisomes – dynamic macromolecular assemblies containing all the enzymatic activities required for synthesis and processing two daughter strands. Genetic and biochemical work has described the composition of the replisome, identifying key enzymes and broadly defining their roles at the replication fork. However, in part due to a lack of direct readouts of replisome function in vivo, the precise roles and dynamic behavior of many replisome components have proved difficult to study in their native context. Additionally, because the genome is a functional biomolecule rather than simply an information storage medium, the DNA double helix is decorated with potential obstacles to replication, and represents a very heterogeneous substrate for replication. The Smith lab seeks to define how the replication machinery overcomes these impediments in order to replicate large, chromatinised genomes.
They use the enrichment and analysis of lagging-strand replication intermediates to study both replisome enzymology and the dynamics of DNA replication in vivo. They predominantly work in the model unicellular eukaryote S. cerevisiae, but have recently begun to apply our genome-wide methods to investigate replication dynamics in human cell lines.
Recent papers:
Osmundson JS, Kumar J, Yeung R, Smith DJ. Pif1-family helicases cooperatively suppress widespread replication-fork arrest at tRNA genes. Nat Struct Mol Biol. 2017 Feb;24(2):162-170. doi: 10.1038/nsmb.3342.
Clausen AR, Lujan SA, Burkholder AB, Orebaugh CD, Williams JS, Clausen MF, Malc EP, Mieczkowski PA, Fargo DC, Smith DJ, Kunkel TA. Tracking replication enzymology in vivo by genome-wide mapping of ribonucleotide incorporation. Nat Struct Mol Biol. 2015 Mar;22(3):185-91. doi: 10.1038/nsmb.2957.
McGuffee SR, Smith DJ, Whitehouse I. Quantitative, genome-wide analysis of eukaryotic replication initiation and termination. Mol Cell. 2013 Apr 11;50(1):123-35. doi: 10.1016/j.molcel.2013.03.004.