Genome stability: From worms to human disease


Session type:

Simon Boulton1
1Cancer Research UK, London Research Institute, South Mimms, UK


Homologous recombination (HR) is an essential conserved process for dividing cells. In mitotic cells, HR is required not only for accurate repair of DNA double-strand breaks (DSBs), but also for the restart of stalled replication forks. Furthermore, HR is crucial for meiotic DSB repair, which is required for accurate chromosome segregation at the first meiotic division. However, inappropriate HR can result in erroneous chromosomal rearrangements and persisting intermediate recombination structures that can drive genome instability and cancer. Therefore, HR must be tightly regulated and temporally coordinated with both replication and cell cycle progression. Current models of eukaryotic HR propose that a DSB is resected to produce 3’ single-stranded DNA tails that are bound by the DNA strand exchange protein RAD51 to form nucleoprotein filaments. These filaments are the catalysts for strand invasion into homologous duplex DNA, resulting in the formation of a D loop structure, whereby the invading 3’ end provides a primer for DNA synthesis and D loop extension. The D loop can be resolved either through displacement of the invading strand and annealing to the other DSB end or by the capture of the other resected end by the extruded strand of the D loop to form a double Holliday junction. Completion of HR by either dissolution or nucleolytic processing followed by ligation yields crossover (CO) or non-crossover (NCO) repair products. Although the mechanics of HR are reasonably well defined at the molecular level, the pathways that regulate COs and NCOs in mitotic and meiotic cells remain poorly understood. In this talk I will present two examples of how we have exploited the power of C. elegans genetics to identify novel DNA repair genes that contribute to genome stability and the prevention of cancer in mammals.