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Transcription-replication conflicts drive R-loop-dependent nucleosome eviction and require DOT1L activity for transcription recovery.
Nucleic Acids Res. 53:gkaf109 (2025)
Progressing transcription and replication machineries profoundly impact their underlying chromatin template. Consequently, transcription-replication conflict (TRC) sites are vulnerable to chromatin and epigenome alterations, provoking genome instability. Here, we engineered an inducible TRC reporter system using a genome-integrated R-loop-prone sequence and characterized the dynamic changes of the local chromatin structure inflicted by TRCs, leading to reduced nucleosome occupancy and replication fork blockage. Strikingly, inducing a small number of TRCs on the genome results in a measurable global replication stress response. Furthermore, we find a TRC-dependent increase in H3K79 methylation specifically at the R-loop forming TRC site. Accordingly, inhibition of the H3K79 methyltransferase DOT1L leads to reduced transcriptional output and an exacerbated DNA damage response, suggesting that deposition of this mark is required for effective transcription recovery and resolution of TRCs. Our work shows the molecular dynamics and reveals a specific epigenetic modifier bookmarking TRC sites, relevant to cancer and other diseases.
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Publication type
Article: Journal article
Document type
Scientific Article
ISSN (print) / ISBN
0305-1048
e-ISSN
1362-4962
Journal
Nucleic Acids Research
Quellenangaben
Volume: 53,
Issue: 4,
Article Number: gkaf109
Publisher
Oxford University Press
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Epigenetics and Stem Cells (IES)