Local regulation of the Srs2 helicase by the SUMO-like domain protein Esc2 promotes recombination at sites of stalled replication
- Madhusoodanan Urulangodi1,
- Marek Sebesta1,2,5,
- Demis Menolfi1,
- Barnabas Szakal1,
- Julie Sollier1,
- Alexandra Sisakova3,4,
- Lumir Krejci2,3,4 and
- Dana Branzei1
- 1FIRC (Fondazione Italiana per la Ricerca sul Cancro) Institute of Molecular Oncology (IFOM), 20139 Milan, Italy;
- 2National Centre for Biomolecular Research, Masaryk University, CZ-62500 Brno, Czech Republic;
- 3Department of Biology, Masaryk University, CZ-62500 Brno, Czech Republic;
- 4International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital Brno, CZ-656 91 Brno, Czech Republic
- Corresponding author: dana.branzei{at}ifom.eu
Abstract
Accurate completion of replication relies on the ability of cells to activate error-free recombination-mediated DNA damage bypass at sites of perturbed replication. However, as anti-recombinase activities are also recruited to replication forks, how recombination-mediated damage bypass is enabled at replication stress sites remained puzzling. Here we uncovered that the conserved SUMO-like domain-containing Saccharomyces cerevisiae protein Esc2 facilitates recombination-mediated DNA damage tolerance by allowing optimal recruitment of the Rad51 recombinase specifically at sites of perturbed replication. Mechanistically, Esc2 binds stalled replication forks and counteracts the anti-recombinase Srs2 helicase via a two-faceted mechanism involving chromatin recruitment and turnover of Srs2. Importantly, point mutations in the SUMO-like domains of Esc2 that reduce its interaction with Srs2 cause suboptimal levels of Rad51 recruitment at damaged replication forks. In conclusion, our results reveal how recombination-mediated DNA damage tolerance is locally enabled at sites of replication stress and globally prevented at undamaged replicating chromosomes.
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Footnotes
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.265629.115.
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Freely available online through the Genes & Development Open Access option.
- Received May 14, 2015.
- Accepted September 3, 2015.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.