Linear interaction between replication and transcription shapes DNA break dynamics at recurrent DNA break Clusters

Lorenzo Corazzi, Vivien S. Ionasz, Sergej Andrejev, Li-Chin Wang, Athanasios Vouzas, Marco Giaisi, Giulia Di Muzio, Boyu Ding, Anna J. M. Marx, Jonas Henkenjohann, Michael M. Allers, David M. Gilbert and Pei-Chi Wei ()
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Lorenzo Corazzi: German Cancer Research Center
Vivien S. Ionasz: German Cancer Research Center
Sergej Andrejev: German Cancer Research Center
Li-Chin Wang: German Cancer Research Center
Athanasios Vouzas: Florida State University
Marco Giaisi: German Cancer Research Center
Giulia Di Muzio: German Cancer Research Center
Boyu Ding: German Cancer Research Center
Anna J. M. Marx: German Cancer Research Center
Jonas Henkenjohann: German Cancer Research Center
Michael M. Allers: German Cancer Research Center
David M. Gilbert: San Diego Biomedical Research Institute
Pei-Chi Wei: German Cancer Research Center

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47934-w

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