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Holliday junction resolution in human cells: two junction endonucleases with distinct substrate specificities

Enzymatic activities that cleave Holliday junctions are required for the resolution of recombination intermediates and for the restart of stalled replication forks. Here we show that human cell‐free extracts possess two distinct endonucleases that can cleave Holliday junctions. The first cleaves Holliday junctions in a structure‐ and sequence‐specific manner, and associates with an ATP‐dependent branch migration activity. Together, these activities promote branch migration/resolution reactions similar to those catalysed by the Escherichia coli RuvABC resolvasome. Like RuvC‐mediated resolution, the products can be religated. The second, containing Mus81 protein, cuts Holliday junctions but the products are mostly non‐ligatable. Each nuclease has a defined substrate specificity: the branch migration‐associated resolvase is highly specific for Holliday junctions, whereas the Mus81‐associated endonuclease is one order of magnitude more active upon replication fork and 3′‐flap structures. Thus, both nucleases are capable of cutting Holliday junctions formed during recombination or through the regression of stalled replication forks. However, the Mus81‐associated endonuclease may play a more direct role in replication fork collapse by catalysing the cleavage of stalled fork structures.