R-loops and nicks initiate DNA breakage and genome instability in non-growing Escherichia coli

Hallie Wimberly, Chandan Shee, P. C. Thornton, Priya Sivaramakrishnan, Susan M. Rosenberg and P. J. Hastings ()
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Hallie Wimberly: 1 Baylor Plaza, Houston, Texas 77030, USA
Chandan Shee: 1 Baylor Plaza, Houston, Texas 77030, USA
P. C. Thornton: 1 Baylor Plaza, Houston, Texas 77030, USA
Priya Sivaramakrishnan: 1 Baylor Plaza, Houston, Texas 77030, USA
Susan M. Rosenberg: 1 Baylor Plaza, Houston, Texas 77030, USA
P. J. Hastings: 1 Baylor Plaza, Houston, Texas 77030, USA

Nature Communications, 2013, vol. 4, issue 1, 1-11

Abstract: Abstract Double-stranded DNA ends, often from replication, drive genomic instability, yet their origin in non-replicating cells is unknown. Here we show that transcriptional RNA/DNA hybrids (R-loops) generate DNA ends that underlie stress-induced mutation and amplification. Depleting RNA/DNA hybrids with overproduced RNase HI reduces both genomic changes, indicating RNA/DNA hybrids as intermediates in both. An Mfd requirement and inhibition by translation implicate transcriptional R-loops. R-loops promote instability by generating DNA ends, shown by their dispensability when ends are provided by I-SceI endonuclease. Both R-loops and single-stranded endonuclease TraI are required for end formation, visualized as foci of a fluorescent end-binding protein. The data suggest that R-loops prime replication forks that collapse at single-stranded nicks, producing ends that instigate genomic instability. The results illuminate how DNA ends form in non-replicating cells, identify R-loops as the earliest known mutation/amplification intermediate, and suggest that genomic instability during stress could be targeted to transcribed regions, accelerating adaptation.

Date: 2013
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DOI: 10.1038/ncomms3115

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