CFAP20 salvages arrested RNAPII from the path of co-directional replisomes
Year: 2026
Type: article
Abstract: 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. CFAP20 has a key role in rescuing RNA polymerase II complexes that have arrested during DNA transcription, limiting the accumulation of R-loops and preventing collisions between the transcription and replication machinery.
Source: Nature
Authors: Sidrit Uruci, Daphne E. C. Boer, Paul W. Chrystal, Maxime Lalonde, Andreas Panagopoulos, George Yakoub, Idil Kirdök, Klaas de Lint, Melanie van der Woude, Tiemen J. Wendel, Sem J. Brussee, Annelotte P. Wondergem, Nila K. van Overbeek, Nini Schotman, Jolanthe Lingeman, Mats Ljungman, Alexander van Oudenaarden, Haico van Attikum, Alfred C. O. Vertegaal, Sylvie M. Noordermeer, Rob M. F. Wolthuis, Matthias Altmeyer, Stephan Hamperl, Vincent Tropepe, Jeroen van den Berg, Diana van den Heuvel, Martijn S. Luijsterburg
Institutions: Leiden University Medical Center, University of Toronto, Helmholtz Munich, Institute of Epigenetics and Stem Cells, University of Zurich, Amsterdam University Medical Centers, Cancer Center Amsterdam, Oncode Institute, University of Michigan, Royal Netherlands Academy of Arts and Sciences, University Medical Center Utrecht, Hubrecht Institute for Developmental Biology and Stem Cell Research
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
OpenAlex ID: W7124153181