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Ummethum, H. ; Murriello, A.C. ; Werner, M. ; Márquez-Gómez, E. ; König, A.-C. ; Kruse, E. ; Lalonde, M. ; Trauner, M. ; Chanou, A. ; Weiß, M. ; Lee, C.S.K. ; Ettinger, A. ; Erhard, F.* ; Hauck, S.M. ; Hamperl, S.

The CGG triplet repeat binding protein 1 counteracts R-loop induced transcription-replication stress.

EMBO Rep. 26, 4691-4722 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
The CGG triplet repeat binding protein 1 (CGGBP1) binds to CGG repeats and has several important cellular functions, but how this DNA sequence-specific binding factor affects transcription and replication processes is an open question. Here, we show that CGGBP1 binds human gene promoters containing short (< 5) CGG-repeat tracts prone to R-loop formation. Loss of CGGBP1 leads to deregulated transcription, transcription-replication-conflicts (TRCs) and accumulation of Serine-5 phosphorylated RNA polymerase II (RNAPII), indicative of promoter-proximal stalling and a defect in transcription elongation. Consistently, an episomal CGG-repeat-containing model locus as well as endogenous genes show deregulated transcription, R-loop accumulation and increased RNAPII chromatin occupancy in CGGBP1-depleted cells. We identify the DEAD-box RNA:DNA helicases DDX41 and DHX15 as interaction partners specifically recruited by CGGBP1. Co-depletion experiments show that DDX41 and CGGBP1 work in the same pathway to unwind R-loops and avoid TRCs. Together, our work shows that short trinucleotide repeats are a source of genome-destabilizing secondary structures, and cells rely on specific DNA-binding factors to maintain proper transcription and replication coordination at short CGG repeats.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Cgg Triplet Repeat Binding Protein 1 ; Cgg-trinucleotide Repeats ; Ddx41 Rna:dna Helicase ; R-loop Structure ; Transcription-replication Conflicts
ISSN (print) / ISBN 1469-221X
e-ISSN 1469-3178
Journal EMBO Reports
Quellenangaben Volume: 26, Issue: 19, Pages: 4691-4722 Article Number: , Supplement: ,
Publisher EMBO Press
Reviewing status Peer reviewed
Institute(s) Institute of Epigenetics and Stem Cells (IES)
CF Metabolomics & Proteomics (CF-MPC)
Grants European Research Council
Helmholtz Association
Deutsche Forschungsgemeinschaft