Journal Article

DKFZ-2026-00960

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Recurrent DNA break clusters drive replication-stress-induced copy number variants and genome diversification.

Corazzi, L. (First author)DKFZ* ; Ing, A. (First author)DKFZ* ; Benito, E. ; Cosenza, M. R. ; Hasenfeld, P. ; Weber, T. ; Marx, A. J. M.DKFZ* ; Ionasz, V.DKFZ* ; Trausch, N.DKFZ* ; Benedetto, S.DKFZ* ; Di Muzio, G.DKFZ* ; Ding, B.DKFZ* ; Berlanda, J.DKFZ* ; Giaisi, M.DKFZ* ; Claudino, N.DKFZ* ; Höfer, T.DKFZ* ; Korbel, J. O.DKFZ* ; Wei, P.-C. (Last author)DKFZ*

2026
Springer Nature [London]

Abstract: Copy number variants (CNVs) are strongly implicated in neurological and psychiatric disorders and brain cancer, yet the process by which replication stress generates CNVs-and why some recur while others remain rare-remains poorly understood. Here, we show that recurrent DNA-break clusters (RDCs) act as common initiating lesions that drive both recurrent and non-recurrent CNVs. In murine neural progenitor cells subjected to chemically induced replication stress, bulk whole-genome sequencing identifies recurrent CNVs enriched at late-replicating RDCs within actively transcribed genes. Single-cell genome sequencing further uncovers frequent, non-recurrent CNVs associated with RDCs that arise during the transition from early to late DNA replication. These CNVs represent stable, heritable structural variants with breakpoints consistently enriched at RDCs. CRISPR/Cas9-mediated transcriptional suppression abolishes both RDC formation and CNV generation, establishing RDC-associated breaks as a shared upstream source. Mechanistically, CNV formation depends on DNA repair context: CNVs are Pol θ-dependent in NHEJ-deficient cells but arise independently of Pol θ in NHEJ-proficient cells. Together, these findings define RDCs as central drivers of replication-stress-induced genome diversification.

Keyword(s): DNA Copy Number Variations: genetics (MeSH) ; Animals (MeSH) ; DNA Replication: genetics (MeSH) ; Mice (MeSH) ; Neural Stem Cells: metabolism (MeSH) ; DNA Breaks (MeSH) ; Genome (MeSH) ; CRISPR-Cas Systems (MeSH) ; Whole Genome Sequencing (MeSH) ; Single-Cell Analysis (MeSH) ; DNA End-Joining Repair: genetics (MeSH) ; Humans (MeSH) ; DNA Repair (MeSH)

Note: #EA:B400#LA:B400#

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Contributing Institute(s):

1. NWG Hirngenom-Mosaizismus und Tumorgenese (B400)
2. B086 Modellierung Biol. Systeme (B086)
3. Mechanismen der genetischen Variation und Datenwissenschaft (B480)

Research Program(s):

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

Appears in the scientific report 2026

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