Journal Article

DKFZ-2024-00895

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Linear interaction between replication and transcription shapes DNA break dynamics at recurrent DNA break Clusters.

Corazzi, L. (First author)DKFZ* ; Ionasz, V. (First author)DKFZ* ; Andrejev, S.DKFZ* ; Wang, L.-C.DKFZ* ; Vouzas, A. ; Giaisi, M.DKFZ* ; Di Muzio, G.DKFZ* ; Ding, B.DKFZ* ; Marx, A.DKFZ* ; Henkenjohann, J.DKFZ* ; Allers, M.DKFZ* ; Gilbert, D. M. ; Wei, P.-C. (Last author)DKFZ*

2024
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-024-47934-w

Abstract: Recurrent DNA break clusters (RDCs) are replication-transcription collision hotspots; many are unique to neural progenitor cells. Through high-resolution replication sequencing and a capture-ligation assay in mouse neural progenitor cells experiencing replication stress, we unravel the replication features dictating RDC location and orientation. Most RDCs occur at the replication forks traversing timing transition regions (TTRs), where sparse replication origins connect unidirectional forks. Leftward-moving forks generate telomere-connected DNA double-strand breaks (DSBs), while rightward-moving forks lead to centromere-connected DSBs. Strand-specific mapping for DNA-bound RNA reveals co-transcriptional dual-strand DNA:RNA hybrids present at a higher density in RDC than in other actively transcribed long genes. In addition, mapping RNA polymerase activity uncovers that head-to-head interactions between replication and transcription machinery result in 60% DSB contribution to the head-on compared to 40% for co-directional. Taken together we reveal TTR as a fragile class and show how the linear interaction between transcription and replication impacts genome stability.

Keyword(s): Animals (MeSH) ; Transcription, Genetic (MeSH) ; DNA Breaks, Double-Stranded (MeSH) ; Mice (MeSH) ; DNA Replication (MeSH) ; Genomic Instability (MeSH) ; Neural Stem Cells: metabolism (MeSH) ; DNA: metabolism (MeSH) ; DNA: genetics (MeSH) ; Replication Origin (MeSH) ; Telomere: metabolism (MeSH) ; Telomere: genetics (MeSH) ; Centromere: metabolism (MeSH) ; Centromere: genetics (MeSH) ; DNA

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Contributing Institute(s):

1. NWG Hirngenom-Mosaizismus und Tumorgenese (B400)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2024

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