Academic Journal
Mitotic DNA synthesis is caused by transcription-replication conflicts in BRCA2-deficient cells
| العنوان: | Mitotic DNA synthesis is caused by transcription-replication conflicts in BRCA2-deficient cells |
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| المؤلفون: | Groelly, FJ, Dagg, RA, Petropoulos, M, Rossetti, GG, Prasad, B, Panagopoulos, A, Paulsen, T, Karamichali, A, Jones, SE, Ochs, F, Dionellis, VS, Puig Lombardi, E, Miossec, MJ, Lockstone, H, Legube, G, Blackford, AN, Altmeyer, M, Halazonetis, TD, Tarsounas, M |
| بيانات النشر: | Cell Press |
| سنة النشر: | 2023 |
| المجموعة: | Oxford University Research Archive (ORA) |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | https://ora.ox.ac.uk/objects/uuid:98c91cf1-6c91-4808-a671-a9b09cb6c0ec; https://doi.org/10.1016/j.molcel.2022.07.011 |
| DOI: | 10.1016/j.molcel.2022.07.011 |
| الاتاحة: | https://doi.org/10.1016/j.molcel.2022.07.011 https://ora.ox.ac.uk/objects/uuid:98c91cf1-6c91-4808-a671-a9b09cb6c0ec |
| Rights: | info:eu-repo/semantics/openAccess ; CC Attribution (CC BY) |
| رقم الانضمام: | edsbas.A4716138 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1016/j.molcel.2022.07.011 |
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