SIRT7 and the DEAD-box helicase DDX21 cooperate to resolve genomic R loops and safeguard genome stability
R loops are three-stranded nucleic acid structures consisting of an RNA:DNA heteroduplex and a “looped-out” nontemplate strand. As aberrant formation and persistence of R loops block transcription elongation and cause DNA damage, mechanisms that resolve R loops are essential for genome stability. He...
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| Main Authors: | , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
August 8, 2017
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| In: |
Genes & development
Year: 2017, Volume: 31, Issue: 13, Pages: 1370-1381 |
| ISSN: | 1549-5477 |
| DOI: | 10.1101/gad.300624.117 |
| Online Access: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1101/gad.300624.117 Verlag, kostenfrei, Volltext: http://genesdev.cshlp.org/content/31/13/1370 
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| Author Notes: | Chenlin Song, Agnes Hotz-Wagenblatt, Renate Voit, and Ingrid Grummt |
| Summary: | R loops are three-stranded nucleic acid structures consisting of an RNA:DNA heteroduplex and a “looped-out” nontemplate strand. As aberrant formation and persistence of R loops block transcription elongation and cause DNA damage, mechanisms that resolve R loops are essential for genome stability. Here we show that the DEAD (Asp-Glu-Ala-Asp)-box RNA helicase DDX21 efficiently unwinds R loops and that depletion of DDX21 leads to accumulation of cellular R loops and DNA damage. Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases. Knockdown of SIRT7 leads to the same phenotype as depletion of DDX21 (i.e., increased formation of R loops and DNA double-strand breaks), indicating that SIRT7 and DDX21 cooperate to prevent R-loop accumulation, thus safeguarding genome integrity. Moreover, DDX21 resolves estrogen-induced R loops on estrogen-responsive genes in breast cancer cells, which prevents the blocking of transcription elongation on these genes. |
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| Item Description: | Published in Advance August 8, 2017 Gesehen am 24.07.2018 |
| Physical Description: | Online Resource |
| ISSN: | 1549-5477 |
| DOI: | 10.1101/gad.300624.117 |