| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Popis: |
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 inBRCA2-mutated breast tumors. Thus, our work provides a mechanism for how tumor-predisposingBRCA2inactivation links transcription-induced DNA damage with mitotic DNA repair to fuel the genomic instability characteristic of cancer cells. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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