DDX17 helicase promotes resolution of R-loop-mediated transcription-replication conflicts in human cells

0567650 - ÚMG 2023 RIV GB eng J - Journal Article
Boleslavská, Barbora - Oravetzová, Anna - Shukla, Kaustubh - Naščáková, Zuzana - Ibini, O. N. - Hašanová, Zdeňka - Andrš, Martin - Kanagaraj, R. - Dobrovolná, Jana - Janščák, Pavel
DDX17 helicase promotes resolution of R-loop-mediated transcription-replication conflicts in human cells.
Nucleic Acids Research. Roč. 50, č. 21 (2022), s. 12274-12290. ISSN 0305-1048. E-ISSN 1362-4962
R&D Projects: GA ČR GA22-08294S; GA ČR GX21-22593X; GA MŠMT LTAUSA19096
Institutional support: RVO:68378050
Keywords : common fragile sites * dna-damage * fork reversal * biotin ligase * rna helicase * stress * phase * yeast * ends * p72
OECD category: Biochemistry and molecular biology
Impact factor: 14.9, year: 2022
Method of publishing: Open access
https://academic.oup.com/nar/article/50/21/12274/6858780?login=true

R-loops are three-stranded nucleic acid structures composed of an RNA:DNA hybrid and displaced DNA strand. These structures can halt DNA replication when formed co-transcriptionally in the opposite orientation to replication fork progression. A recent study has shown that replication forks stalled by co-transcriptional R-loops can be restarted by a mechanism involving fork cleavage by MUS81 endonuclease, followed by ELL-dependent reactivation of transcription, and fork religation by the DNA ligase IV (LIG4)/XRCC4 complex. However, how R-loops are eliminated to allow the sequential restart of transcription and replication in this pathway remains elusive. Here, we identified the human DDX17 helicase as a factor that associates with R-loops and counteracts R-loop-mediated replication stress to preserve genome stability. We show that DDX17 unwinds R-loops in vitro and promotes MUS81-dependent restart of R-loop-stalled forks in human cells in a manner dependent on its helicase activity. Loss of DDX17 helicase induces accumulation of R-loops and the formation of R-loop-dependent anaphase bridges and micronuclei. These findings establish DDX17 as a component of the MUS81-LIG4-ELL pathway for resolution of R-loop-mediated transcription-replication conflicts, which may be involved in R-loop unwinding.
Permanent Link: https://hdl.handle.net/11104/0338874