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

Fine-tuning DNA replication and transcription is crucial to prevent collisions between their machineries<sup>1</sup>. This is particularly important near promoters, where RNA polymerase II (RNAPII) initiates transcription and frequently arrests, forming R-loops<sup>2-4</sup>. Arrested RNAPII can obstruct DNA replication, which often initiates near promoters<sup>5,6</sup>. 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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Journal
Nature
Published
2026-01-14
DOI
https://doi.org/10.1038/s41586-025-09943-7
Primary Topic
DNA Repair Mechanisms
Type
article
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article

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

Martijn S. Luijsterburg, Sem Brussee, George Yakoub, Maxime Lalonde et al.
Nature
DNA Repair Mechanisms
article

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

Martijn S. Luijsterburg, Sem Brussee, George Yakoub, Maxime Lalonde, İdil Kirdök, Sylvie M. Noordermeer, Jeroen van den Berg, Paul Chrystal, Mats Ljungman, Klaas de Lint, Sidrit Uruci, Melanie van der Woude, Diana van den Heuvel, Tiemen J. Wendel, Annelotte P. Wondergem, Vincent Tropepe, Matthias Altmeyer, Nila van Overbeek, Haico van Attikum, Jolanthe Lingeman, Andreas Panagopoulos, Stephan Hamperl, Rob M. F. Wolthuis, Nini Schotman, Daphne E. C. Boer, Alfred C. O. Vertegaal
article en

Abstract

Fine-tuning DNA replication and transcription is crucial to prevent collisions between their machineries<sup>1</sup>. This is particularly important near promoters, where RNA polymerase II (RNAPII) initiates transcription and frequently arrests, forming R-loops<sup>2-4</sup>. Arrested RNAPII can obstruct DNA replication, which often initiates near promoters<sup>5,6</sup>. 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.

NatureVol. 650(8103)
University of Toronto (CA), University of Zurich (CH), University of Michigan (US), Leiden University Medical Center (NL), Helmholtz Zentrum München (DE), University Medical Center Utrecht (NL), Oncode Institute (NL), Hubrecht Institute for Developmental Biology and Stem Cell Research (NL), Amsterdam University Medical Centers (NL), University of Amsterdam (NL)
Openalex Percentile: Top 88%
DNA Repair Mechanisms
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