Human Mus81-associated endonuclease cleaves holliday junctions in vitro

Mus81, a protein with homology to the XPF subunit of the ERCC1-XPF endonuclease, is important for replicational stress tolerance in both budding and fission yeast. Human Mus8l has associated endonuclease activity against structure-specific oligonucleotide substrates, including synthetic Holliday junctions. Mus81-associated endonuclease resolves Holliday junctions into linear duplexes by cutting across the junction exclusively on strands of like polarity. In addition, Mus8l protein abundance increases in cells following exposure to agents that block DNA replication. Taken together, these findings suggest a role for Mus8l in resolving Holliday junctions that arise when DNA replication is blocked by damage or by nucleotide depletion. Mus8l is not related by sequence to previously characterized Holliday junction resolving enzymes, and it has distinct enzymatic properties that suggest it uses a novel enzymatic strategy to cleave Holliday junctions.