Journal
MOLECULAR CELL
Volume 65, Issue 5, Pages 848-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2017.01.031
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Funding
- Cancer Research UK
- Francis Crick Institute [FC10212]
- European Research Council [ERC-ADG-249145, ERC-ADG-666400]
- Louis-Jeantet Foundation
- Medical Research Council
- Wellcome Trust
- Natural Sciences and Engineering Research Council of Canada
- US NIH Protein Structure Initiative [P50-GM62413-02]
- Canadian Institutes of Health Research through the Canada Research Chairs program
- Cancer Research UK [11582] Funding Source: researchfish
- Cancer Research UK
- The Francis Crick Institute [10015] Funding Source: researchfish
- The Francis Crick Institute [10368, 10212, 10216, 10213] Funding Source: researchfish
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The efficient removal of replication and recombination intermediates is essential for the maintenance of genome stability. Resolution of these potentially toxic structures requires the MUS81-EME1 endonuclease, which is activated at prometaphase by formation of the SMX tri-nuclease containing three DNA repair structure-selective endonucleases: SLX1-SLX4, MUS81-EME1, and XPF-ERCC1. Here we show that SMX tri-nuclease is more active than the three individual nucleases, efficiently cleaving replication forks and recombination intermediates. Within SMX, SLX4 co-ordinates the SLX1 and MUS81-EME1 nucleases for Holliday junction resolution, in a reaction stimulated by XPF-ERCC1. SMX formation activates MUS81-EME1 for replication fork and flap structure cleavage by relaxing substrate specificity. Activation involves MUS81's conserved N-terminal HhH domain, which mediates incision site selection and SLX4 binding. Cell cycle-dependent formation and activation of this tri-nuclease complex provides a unique mechanism by which cells ensure chromosome segregation and preserve genome integrity.
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