John F.X. Diffley

The Work:

Our very large genomes must be accurately replicated in each cell cycle, no part of the genome should be replicated more than once and replication must be completed before cell division. Using budding yeast as a model organism, Diffley has shown in molecular detail how DNA replication origins are regulated to ensure once per cell cycle replication. His laboratory has reconstituted the entire chromatin replication pathway using purified proteins. This has led to an understanding of how the replicative DNA helicase is loaded at origins, how it is activated, how it nucleates assembly of the replication machinery and how the replication machinery displaces and re-deposits nucleosomes during replication. He has also shown that DNA damage checkpoints regulate DNA replication on damaged DNA templates by inhibiting replication origin firing and promoting replication fork stability.

The Impact:

Each time a cell divides, it must copy its DNA equally into two new cells. If the cell’s DNA is not copied precisely before it divides, new cells end up without necessary genetic information which can prevent their division, lead to cell death, or cause many cells to divide out of control, forming a tumour.

By describing the exact sequence of events involved in DNA replication, Stillman and Diffley have provided key insights into how our genome is duplicated and how this process is coordinated with many other essential cellular events, which have implications for understanding genome instability and tumour heterogeneity in cancer.