Branchpoint translocation by fork remodelers as a general mechanism of R-loop removal.
Date
2022-12-06ICR Author
Author
Hodson, C
van Twest, S
Dylewska, M
O'Rourke, JJ
Tan, W
Murphy, VJ
Walia, M
Abbouche, L
Nieminuszczy, J
Dunn, E
Bythell-Douglas, R
Heierhorst, J
Niedzwiedz, W
Deans, AJ
Type
Journal Article
Metadata
Show full item recordAbstract
Co-transcriptional R loops arise from stalling of RNA polymerase, leading to the formation of stable DNA:RNA hybrids. Unresolved R loops promote genome instability but are counteracted by helicases and nucleases. Here, we show that branchpoint translocases are a third class of R-loop-displacing enzyme in vitro. In cells, deficiency in the Fanconi-anemia-associated branchpoint translocase FANCM causes R-loop accumulation, particularly after treatment with DNA:RNA-hybrid-stabilizing agents. This correlates with FANCM localization at R-loop-prone regions of the genome. Moreover, other branchpoint translocases associated with human disease, such as SMARCAL1 and ZRANB3, and those from lower organisms can also remove R loops in vitro. Branchpoint translocases are more potent than helicases in resolving R loops, indicating their evolutionary important role in R-loop suppression. In human cells, FANCM, SMARCAL1, and ZRANB3 depletion causes additive effects on R-loop accumulation and DNA damage. Our work reveals a mechanistic basis for R-loop displacement that is linked to genome stability.
Collections
Subject
CP: Molecular biology
DNA:RNA hybrid
Fanconi anemia
R loop
genome stability
human disease
transcription
translocation
Humans
R-Loop Structures
RNA
DNA Helicases
Research team
Cancer and Genome Instab
Language
eng
Date accepted
2022-11-09
License start date
2022-12-06
Citation
Cell Reports, 2022, 41 (10), pp. 111749 -
Publisher
CELL PRESS