Holliday Junction Resolvases: the Good, the Bad and the Ugly

Abstract

In simple organisms, Holliday junctions (HJs) that arise during recombination and the recombinational repair of DNA are resolved by a junction‐specific endonuclease activity. For example, in E. coli, the RuvC protein specifically recognises and binds HJs, and then promotes their cleavage by the introduction of symmetrically‐related nicks across the junction point. The resulting nicked duplexes can then be religated.In contrast, mitotic eukaryotic cells appear to have evolved a rather different mechanism of resolution, because in humans the removal of HJs is preferentially mediated by the BTR complex (BLM‐TopoIIIα‐ RMI1–RMI2), which combines DNA helicase and topoisomerase activities to bring about HJ ‘dissolution’. The benefit of this mechanism of HJ processing is that recombination events that link homologous chromosomes are guaranteed to be resolved to form non‐crossovers, thereby avoiding crossovers and the potential for loss of heterozygosity (LOH) of tumour suppressor genes ‐ a hallmark feature of cancer cells.Given the importance of avoiding crossovers, it is perhaps surprising that mitotic cells encode three junction‐specific nucleases that can resolve HJs to form crossovers. In humans, these are MUS81‐EME1, SLX1‐SLX4 and GEN1. How these nucleases are controlled, in order to avoid crossover formation, has revealed unexpected insights into mechanisms of Holliday junction processing.