SIRT7 and the DEAD-box helicase DDX21 cooperate to resolve genomic R loops and safeguard genome stability

• Verfasst von: Song, Chenlin [VerfasserIn]
• Verfasst von: Hotz-Wagenblatt, Agnes [VerfasserIn]
• Verfasst von: Voit, Renate [VerfasserIn]
• Verfasst von: Grummt, Ingrid [VerfasserIn]
• Titel: SIRT7 and the DEAD-box helicase DDX21 cooperate to resolve genomic R loops and safeguard genome stability
• Verf.angabe: Chenlin Song, Agnes Hotz-Wagenblatt, Renate Voit, and Ingrid Grummt
• E-Jahr: 2017
• Jahr: August 8, 2017
• Umfang: 12 S.
• Fussnoten: Published in Advance August 8, 2017 ; Gesehen am 24.07.2018
• Titel Quelle: Enthalten in: Genes & development
• Ort Quelle: Stanford, Calif. : HighWire Press, 1987
• Jahr Quelle: 2017
• Band/Heft Quelle: 31(2017), 13, Seite 1370-1381
• ISSN Quelle: 1549-5477
• DOI: doi:10.1101/gad.300624.117
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: acetylation
• Sach-SW: DDX21 helicase
• Sach-SW: DNA damage
• Sach-SW: R loops
• Sach-SW: SIRT7
• Sach-SW: transcription
• K10plus-PPN: 1577879414

Abstract

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.