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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5580657/ https://www.ncbi.nlm.nih.gov/pubmed/28790157 http://dx.doi.org/10.1101/gad.300624.117 |
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author | Song, Chenlin Hotz-Wagenblatt, Agnes Voit, Renate Grummt, Ingrid |
author_facet | Song, Chenlin Hotz-Wagenblatt, Agnes Voit, Renate Grummt, Ingrid |
author_sort | Song, Chenlin |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5580657 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-55806572018-01-01 SIRT7 and the DEAD-box helicase DDX21 cooperate to resolve genomic R loops and safeguard genome stability Song, Chenlin Hotz-Wagenblatt, Agnes Voit, Renate Grummt, Ingrid Genes Dev Research Paper 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. Cold Spring Harbor Laboratory Press 2017-07-01 /pmc/articles/PMC5580657/ /pubmed/28790157 http://dx.doi.org/10.1101/gad.300624.117 Text en © 2017 Song et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Research Paper Song, Chenlin Hotz-Wagenblatt, Agnes Voit, Renate Grummt, Ingrid SIRT7 and the DEAD-box helicase DDX21 cooperate to resolve genomic R loops and safeguard genome stability |
title | SIRT7 and the DEAD-box helicase DDX21 cooperate to resolve genomic R loops and safeguard genome stability |
title_full | SIRT7 and the DEAD-box helicase DDX21 cooperate to resolve genomic R loops and safeguard genome stability |
title_fullStr | SIRT7 and the DEAD-box helicase DDX21 cooperate to resolve genomic R loops and safeguard genome stability |
title_full_unstemmed | SIRT7 and the DEAD-box helicase DDX21 cooperate to resolve genomic R loops and safeguard genome stability |
title_short | SIRT7 and the DEAD-box helicase DDX21 cooperate to resolve genomic R loops and safeguard genome stability |
title_sort | sirt7 and the dead-box helicase ddx21 cooperate to resolve genomic r loops and safeguard genome stability |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5580657/ https://www.ncbi.nlm.nih.gov/pubmed/28790157 http://dx.doi.org/10.1101/gad.300624.117 |
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