Mechanisms underlying genome instability mediated by formation of foldback inversions in Saccharomyces cerevisiae

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Abstract

Foldback inversions, also called inverted duplications, have been observed in human genetic diseases and cancers. Here we used a Saccharomyces cerevisiae genetic system that generates gross chromosomal rearrangements (GCRs) mediated by foldback inversions combined with whole-genome sequencing to study their formation. Foldback inversions were mediated by formation of single-stranded DNA hairpins. Two types of hairpins were identified: small-loop hairpins that were suppressed by MRE11, SAE2, SLX1, and YKU80 and large-loop hairpins that were suppressed by YEN1, TEL1, SWR1, and MRC1. Analysis of CRISPR/Cas9-induced double strand breaks (DSBs) revealed that long-stem hairpin-forming sequences could form foldback inversions when proximal or distal to the DSB, whereas short-stem hairpin-forming sequences formed foldback inversions when proximal to the DSB. Finally, we found that foldback inversion GCRs were stabilized by secondary rearrangements, mostly mediated by different homologous recombination mechanisms including single-strand annealing; however, POL32-dependent break-induced replication did not appear to be involved forming secondary rearrangements.

Data availability

Sequencing data is available from National Center for Biotechnology Information Sequence Read Archive under accession number PRJNA627970.All other data generated are included in the manuscript and supporting files.

The following data sets were generated

(2020) Saccharomyces cerevisiae foldback inversion GCR sequencing, Apr 21, 2020
Sequence Read Archive https://www.ncbi.nlm.nih.gov/sra.

https://www.ncbi.nlm.nih.gov/bioproject/PRJNA627970

Article and author information

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Bin-zhong Li

Cancer Genetics, Ludwig Institute for Cancer Research, UCSD, La Jolla, United States

Competing interests
The authors declare that no competing interests exist.
Christopher D Putnam

Medicine, UCSD, Ludwig Institute for Cancer Research, UCSD, La Jolla, United States

For correspondence
cdputnam@ucsd.edu

Competing interests
The authors declare that no competing interests exist.
Richard David Kolodner

Cancer Genetics, Ludwig Institute for Cancer Research, UCSD, La Jolla, United States

For correspondence
rkolodner@health.ucsd.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-4806-8384

Funding

National Institute of General Medical Sciences (GM26017)

Richard David Kolodner

Ludwig Institute for Cancer Research (Lab Funding)

Bin-zhong Li
Christopher D Putnam
Richard David Kolodner

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.