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Uruci, S.* ; Boer, D.E.C.* ; Chrystal, P.* ; Lalonde, M. ; Panagopoulos, A.* ; Yakoub, G.* ; Kirdök, I.* ; Lint, K.d.* ; Woude, M.v.d.* ; Wendel, T.J.* ; Brussee, S.* ; Wondergem, A.P.* ; Overbeek, N.v.* ; Schotman, N.* ; Lingeman, J.* ; Ljungman, M.* ; Vidal, M.* ; Attikum, H.v.* ; Vertegaal, A.C.O.* ; Noordermeer, S.M.* ; Wolthuis, R.M.F.* ; Altmeyer, M.* ; Hamperl, S. ; Tropepe, V.* ; Berg, J.v.d.* ; Heuvel, D.v.d.* ; Luijsterburg, M.S.*

CFAP20 salvages arrested RNAPII from the path of co-directional replisomes.

Nature 650, 1025-1034 (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Fine-tuning DNA replication and transcription is crucial to prevent collisions between their machineries1. This is particularly important near promoters, where RNA polymerase II (RNAPII) initiates transcription and frequently arrests, forming R-loops2-4. Arrested RNAPII can obstruct DNA replication, which often initiates near promoters5,6. The mechanisms that rescue arrested RNAPII during elongation to avoid conflicts with co-directional replisomes remain unclear. Here, using genome-wide approaches and genetic screens, we identify CFAP20 as part of a protective pathway that salvages arrested RNAPII in promoter-proximal regions, diverting it from the path of co-directional replisomes. CFAP20-deficient cells accumulate R-loops near promoters, which leads to defects in replication timing and dynamics. These defects stem from accelerated replication-fork speeds that cause a secondary reduction in origin activity. Co-depletion of the Mediator complex or removal of R-loop-engaged RNAPII restores normal replication. Our findings suggest that transcription-dependent fork stalling in cis induces accelerated fork progression in trans, generating single-stranded DNA gaps. We propose that CFAP20 facilitates RNAPII elongation under high levels of Mediator-driven transcription, thereby preventing replisome collisions. This study provides a transcription-centred view of transcription-replication encounters, revealing how locally arrested transcription complexes propagate genome-wide replication phenotypes and defining CFAP20 as a key factor that safeguards genome stability.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Polymerase-ii; Computational Platform; Replication; Genes; Elongation; Hub
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Zeitschrift Nature
Quellenangaben Band: 650, Heft: 8103, Seiten: 1025-1034 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Epigenetics and Stem Cells (IES)
Förderungen Swiss National Science Foundation
ERC
Netherlands Scientific Organization
ADORE Foundation
Netherlands Scientific Organization (NWO Vidi)
Dutch Cancer Foundation
Oncode Institute
Canadian Institutes of Health Research
National Human Genome Research Institute
National Cancer Institute
Netherlands Scientific Organization Vici grant