Break-induced replication promotes formation of lethal joint molecules dissolved by Srs2

Rajula Elango, Ziwei Sheng, Jessica Jackson, Jenna DeCata, Younis Ibrahim, Nhung T. Pham, Diana H. Liang, Cynthia J. Sakofsky, Alessandro Vindigni, Kirill S. Lobachev (), Grzegorz Ira () and Anna Malkova ()
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Rajula Elango: University of Iowa
Ziwei Sheng: Georgia Institute of Technology
Jessica Jackson: Saint Louis University School of Medicine
Jenna DeCata: University of Iowa
Younis Ibrahim: University of Iowa
Nhung T. Pham: Baylor College of Medicine
Diana H. Liang: Baylor College of Medicine
Cynthia J. Sakofsky: University of Iowa
Alessandro Vindigni: Saint Louis University School of Medicine
Kirill S. Lobachev: Georgia Institute of Technology
Grzegorz Ira: Baylor College of Medicine
Anna Malkova: University of Iowa

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Break-induced replication (BIR) is a DNA double-strand break repair pathway that leads to genomic instabilities similar to those observed in cancer. BIR proceeds by a migrating bubble where asynchrony between leading and lagging strand synthesis leads to accumulation of long single-stranded DNA (ssDNA). It remains unknown how this ssDNA is prevented from unscheduled pairing with the template, which can lead to genomic instability. Here, we propose that uncontrolled Rad51 binding to this ssDNA promotes formation of toxic joint molecules that are counteracted by Srs2. First, Srs2 dislodges Rad51 from ssDNA preventing promiscuous strand invasions. Second, it dismantles toxic intermediates that have already formed. Rare survivors in the absence of Srs2 rely on structure-specific endonucleases, Mus81 and Yen1, that resolve toxic joint-molecules. Overall, we uncover a new feature of BIR and propose that tight control of ssDNA accumulated during this process is essential to prevent its channeling into toxic structures threatening cell viability.

Date: 2017
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DOI: 10.1038/s41467-017-01987-2

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