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Deletions and chromosome re-arrangements are common features of cancer cells. We have established a new two-component system reporting on epigenetic silencing or deletion of an actively transcribed gene adjacent to a double-strand break (DSB). Unexpectedly, we find that a targeted DSB results in a minority (<10%) misrepair event of kilobase deletions encompassing the DSB site and transcribed gene. Deletions are reduced upon RNaseH1 over-expression and increased after knockdown of the DNA:RNA helicase Senataxin, implicating a role for DNA:RNA hybrids. We further demonstrate that the majority of these large deletions are dependent on the 3' flap endonuclease XPF. DNA:RNA hybrids were detected by DNA:RNA immunoprecipitation in our system after DSB generation. These hybrids were reduced by RNaseH1 over-expression and increased by Senataxin knock-down, consistent with a role in deletions. Overall, these data are consistent with DNA:RNA hybrid generation at the site of a DSB, mis-processing of which results in genome instability in the form of large deletions.

Original publication

DOI

10.1038/s41598-018-21806-y

Type

Journal article

Journal

Sci Rep

Publication Date

01/03/2018

Volume

8

Keywords

Cell Line, Tumor, DNA, DNA Breaks, Double-Stranded, DNA Helicases, DNA Repair, DNA-Binding Proteins, Endonucleases, Genomic Instability, Humans, Multifunctional Enzymes, RNA, RNA Helicases, Sequence Deletion