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Scientific article
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English

Mitotic DNA synthesis is caused by transcription-replication conflicts in BRCA2-deficient cells

Published inMolecular cell, vol. 82, no. 18, p. 3382-3397.e7
Publication date2022-09-15
First online date2022-08-23
Abstract

Aberrant replication causes cells lacking BRCA2 to enter mitosis with under-replicated DNA, which activates a repair mechanism known as mitotic DNA synthesis (MiDAS). Here, we identify genome-wide the sites where MiDAS reactions occur when BRCA2 is abrogated. High-resolution profiling revealed that these sites are different from MiDAS at aphidicolin-induced common fragile sites in that they map to genomic regions replicating in the early S-phase, which are close to early-firing replication origins, are highly transcribed, and display R-loop-forming potential. Both transcription inhibition in early S-phase and RNaseH1 overexpression reduced MiDAS in BRCA2-deficient cells, indicating that transcription-replication conflicts (TRCs) and R-loops are the source of MiDAS. Importantly, the MiDAS sites identified in BRCA2-deficient cells also represent hotspots for genomic rearrangements in BRCA2-mutated breast tumors. Thus, our work provides a mechanism for how tumor-predisposing BRCA2 inactivation links transcription-induced DNA damage with mitotic DNA repair to fuel the genomic instability characteristic of cancer cells.

eng
Keywords
  • BRCA2
  • MiDAS
  • R-loops
  • TRCs
  • Genome stability
  • Mitotic DNA synthesis
  • Transcription-replication conflicts
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Citation (ISO format)
GROELLY, Florian J. et al. Mitotic DNA synthesis is caused by transcription-replication conflicts in BRCA2-deficient cells. In: Molecular cell, 2022, vol. 82, n° 18, p. 3382–3397.e7. doi: 10.1016/j.molcel.2022.07.011
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ISSN of the journal1097-2765
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