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Mol Cell. 2015 Dec 17;60(6):835-46. doi: 10.1016/j.molcel.2015.10.023. Epub 2015 Nov 19.

Essential Roles of the Smc5/6 Complex in Replication through Natural Pausing Sites and Endogenous DNA Damage Tolerance.

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IFOM, the FIRC Institute of Molecular Oncology, Via Adamello 16, 20139, Milan, Italy.
IGH, Institute of Human Genetics CNRS UPR 1142, 141 rue de la Cardonille F-34396 Cedex 5, Montpellier, France.
IFOM, the FIRC Institute of Molecular Oncology, Via Adamello 16, 20139, Milan, Italy. Electronic address:


The essential functions of the conserved Smc5/6 complex remain elusive. To uncover its roles in genome maintenance, we established Saccharomyces cerevisiae cell-cycle-regulated alleles that enable restriction of Smc5/6 components to S or G2/M. Unexpectedly, the essential functions of Smc5/6 segregated fully and selectively to G2/M. Genetic screens that became possible with generated alleles identified processes that crucially rely on Smc5/6 specifically in G2/M: metabolism of DNA recombination structures triggered by endogenous replication stress, and replication through natural pausing sites located in late-replicating regions. In the first process, Smc5/6 modulates remodeling of recombination intermediates, cooperating with dissolution activities. In the second, Smc5/6 prevents chromosome fragility and toxic recombination instigated by prolonged pausing and the fork protection complex, Tof1-Csm3. Our results thus dissect Smc5/6 essential roles and reveal that combined defects in DNA damage tolerance and pausing site-replication cause recombination-mediated DNA lesions, which we propose to drive developmental and cancer-prone disorders.

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