Essential Roles of the Smc5/6 Complex in Replication through Natural Pausing Sites and Endogenous DNA Damage Tolerance
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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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The model of the Siz2 and Mms21 SUMO ligase complex suggests that both E3s could act jointly to modify DNA associated substrates perhaps through the DNA binding SAP domain of Siz2 or involving the Mms21 (Nse2) containing Smc5-6 complex.
“Our model of the Siz2 and Mms21 SUMO ligase complex (fig. S21A) suggests that both E3s could act jointly to modify DNA associated substrates perhaps through the DNA binding SAP domain of Siz2 (53) or involving the Mms21 (Nse2) containing Smc5–6 complex which modulates DNA recombination, replication and repair (54,55).”
From Computed structures of core eukaryotic protein complexes (2021) · cites this paper as [54]
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References 57 · Cited by 110
- Authors
- Menolfi, D., Delamarre, A., Lengronne, A., Pasero, P., & Branzei, D.
- Affiliations
- IFOM (IT)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Branzei, Dana
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2015-12
- Volume
- 60
- Issue
- 6
- Pages
- 835-846
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4691243
- OpenAlex
- W2220643462
- Cited by
- 110
- References
- 57
- Citations by year
- 2026: 9 · 2025: 2 · 2024: 12 · 2023: 8 · 2022: 5 · 2021: 16 · 2020: 13 · 2019: 9 · 2018: 13 · 2017: 10 · 2016: 11 · 2015: 2
- FWCI
- 5.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Molecular Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-14-CE10-0010)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- Smc5/6 complex, DNA damage tolerance, late-replicating regions, chromosome fragility, genome maintenance, Saccharomyces cerevisiae
- MeSH terms
- Cell Cycle, DNA Damage, DNA Replication, DNA-Binding Proteins, DNA, Fungal, Genetic Testing, Recombination, Genetic, Saccharomyces cerevisiae, Gene Expression Regulation, Fungal, Cell Cycle Proteins, Genes, Essential, Saccharomyces cerevisiae Proteins
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