Transcription-replication conflict resolution by nuclear RNA interference
Nuclear RNA interference (RNAi) is required for heterochromatin silencing, but Dicer also promotes genome stability by releasing RNA polymerase at sites of replication stress. R-loops are three-stranded DNA:RNA structures that accumulate at transcription-replication (T-R) collisions. We show that in RNase H-deficient cells, which accumulate pathological R-loops, Dcr1 processes R-loops at transcriptional start sites (TSSs) and end sites (TESs), releasing paused RNA polymerase and accounting for small RNAs (sRNAs) resembling DNA-damage-associated sense sRNAs (sdRNAs) found in cancer cells. Genetic evidence implicates nascent transcription-associated R-loops in genome instability in the absence of Dicer, with the helicase domain providing catalytic function reminiscent of related archaeal helicases involved in replication. The RNase H homolog Argonaute (Ago1) promotes genome instability by binding R-loops, and its removal relieves replication stress. Analysis of replication intermediates, DNA and RNA 3' ends, and fork processivity genome wide indicates Dicer resolves head-on T-R collisions, consistent with an ancient origin in DNA replication.
Authors
- Leila Touat‐Todeschini (ORCID: https://orcid.org/0000-0002-6064-7362)
- Sarah Lambert (ORCID: https://orcid.org/0000-0002-1403-3204)
- Teri Cheng (ORCID: https://orcid.org/0000-0002-8781-0203)
- Robert A. Martienssen (ORCID: https://orcid.org/0000-0003-1285-9608)
- André Verdel (ORCID: https://orcid.org/0000-0001-6048-3794)
- Karine Fréon (ORCID: https://orcid.org/0000-0001-7853-078X)
- Benjamin Roche (ORCID: https://orcid.org/0000-0003-3912-6340)
- Asad A. Lakhani (ORCID: https://orcid.org/0000-0001-9663-6051)
- Jie Ren (ORCID: https://orcid.org/0000-0002-6450-3163)
- Christine Choi (ORCID: https://orcid.org/0000-0001-8786-9304)
- Sonali Bhattacharjee (ORCID: https://orcid.org/0000-0003-0522-3361)
- Farida Abderahmane
- Liam G. Spielmann
- Emerson Jenen
Institutions
- Centre National de la Recherche Scientifique (FR)
- Howard Hughes Medical Institute (US)
- Inserm (FR)
- Université Paris Sciences et Lettres (FR)
- Cold Spring Harbor Laboratory (US)
- Université Paris-Saclay (FR)
- La Ligue Contre le Cancer (FR)
- Immunité et Cancer (FR)
- Institut de Biosciences et Biotechnologies (FR)
- Institut pour l'avancée des biosciences (FR)
- Université Grenoble Alpes (FR)
Publication Details
- Journal
- Molecular Cell
- Published
- 2025-10-28
- DOI
- https://doi.org/10.1016/j.molcel.2025.10.003
- Citations
- 1
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.81