Branchpoint translocation by fork remodelers as a general mechanism of R-loop removal.
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ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2022-12-06
Date Accepted
2022-11-09
Abstract
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.
Citation
Cell Reports, 2022, 41 (10), pp. 111749 -
Source Title
Cell Reports
Publisher
CELL PRESS
ISSN
2211-1247
eISSN
2211-1247
2211-1247
2211-1247
Collections
Research Team
Cancer and Genome Instab