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; Anna Malkova

doi:10.1038/s41467-017-01987-2

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

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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, …

Nature communications, Vol.8(1), pp.1790-13

11/27/2017

DOI: 10.1038/s41467-017-01987-2

PMCID: PMC5702615

PMID: 29176630

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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.

Details

Title: Subtitle: Break-induced replication promotes formation of lethal joint molecules dissolved by Srs2
Creators: Rajula Elango - Department of Biology, University of Iowa, Iowa City, IA, 52242, USA
Ziwei Sheng - School of Biological Sciences and Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA
Jessica Jackson - Edward A Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, 63103, USA
Jenna DeCata - Department of Biology, University of Iowa, Iowa City, IA, 52242, USA
Younis Ibrahim - Department of Biology, University of Iowa, Iowa City, IA, 52242, USA
Nhung T Pham - Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
Diana H Liang - Houston Methodist Hospital, 6565 Fannin St., Houston, TX, 77030, USA
Cynthia J Sakofsky - Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, Durham, NC, 27709, USA
Alessandro Vindigni - Edward A Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, 63103, USA
Kirill S Lobachev - School of Biological Sciences and Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA. kirill.lobachev@biology.gatech.edu
Grzegorz Ira - Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. gira@bcm.edu
Anna Malkova - Department of Biology, University of Iowa, Iowa City, IA, 52242, USA. anna-malkova@uiowa.edu
Resource Type: Journal article
Publication Details: Nature communications, Vol.8(1), pp.1790-13
DOI: 10.1038/s41467-017-01987-2
PMID: 29176630
PMCID: PMC5702615
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Language: English
Date published: 11/27/2017
Academic Unit: Biology
Record Identifier: 9984217418502771

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