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Vol. 14, Issue 12, 4826-4834, December 2003

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Mus81 Endonuclease Localizes to Nucleoli and to Regions of DNA Damage in Human S-phase Cells

Hui Gao, Xiao-Bo Chen ^*, and Clare H. McGowan 

Department of Molecular Biology and Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037

Submitted May 5, 2003; Revised July 9, 2003; Accepted July 26, 2003
Monitoring Editor: Frank Solomon

Mus81 is a highly conserved substrate specific endonuclease. Human Mus81 cleaves Holliday junctions, replication forks, and 3' flap substrates in vitro, suggesting a number of possible in vivo functions. We show here that the abundance of human Mus81 peaks in S-phase and remains high in cells that have completed DNA replication and that Mus81 is a predominantly nuclear protein, with super accumulation in nucleoli. Two RecQ related DNA helicases BLM and WRN that are required for recombination repair in human cells colocalize with Mus81 in nucleoli. However, the nucleolar retention of Mus81 is not dependent on the presence of BLM or WRN, or on ongoing transcription. Mus81 is recruited to localized regions of UV damage in S-phase cells, but not in cells that are blocked from replicating DNA or that have completed replication. The retention of human Mus81 at regions of UV-induced damage specifically in S-phase cells suggest that the enzyme is recruited to the sites at which replication forks encounter damaged DNA. The nucleolar concentration of Mus81 suggests that it is required to repair problems that arise most frequently in the highly repetitive nucleolar DNA. Together these data support a role for Mus81 in recombination repair in higher eukaryotes.

^* Present address: Program of Molecular Genetics, The University of Arizona Cancer Center 0975A, 1515 N. Campbell Avenue, Tucson, AZ 85724.

Corresponding author. E-mail address: chmcg{at}scripps.edu.

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