biostudies-literatureUmmethum HDeutsche Forschungsgemeinschaft (DFG)Deutsche ForschungsgemeinschaftEuropean Research CouncilHelmholtz Association4691-4722https://www.ebi.ac.uk/biostudies/studies/S-EPMC12508481biostudies-literatureUnknown26(19)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-depEMBO reportsThe CGG triplet repeat binding protein 1 counteracts R-loop induced transcription-replication stress.PMC12508481852798CRC1064,project ID 213249687Werner MErhard FChanou AWeiβ MKruse EHauck SMKonig ACTrauner MHamperl SLalonde MMurriello ACLee CSKUmmethum HMarquez-Gomez EEttinger AfalseThe CGG triplet repeat binding protein 1 counteracts R-loop induced transcription-replication stress.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-dep2025-01-01T00:00:00Z2025 Oct2026-06-04T10:13:13.52Z2026-05-08T03:10:30.651ZS-EPMC125084814085901110.1038/s44319-025-00550-1