Mitotic DNA synthesis is caused by transcription-replication conflicts in BRCA2-deficient cells
<p>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 revea...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Cell Press
2022
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| _version_ | 1826309905031626752 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Groelly, FJ |
| collection | OXFORD |
| description | <p>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 <em>BRCA2</em>-mutated breast tumors. Thus, our work provides a mechanism for how tumor-predisposing <em>BRCA2</em> inactivation links transcription-induced DNA damage with mitotic DNA repair to fuel the genomic instability characteristic of cancer cells.</p> |
| first_indexed | 2024-03-07T07:42:43Z |
| format | Journal article |
| id | oxford-uuid:98c91cf1-6c91-4808-a671-a9b09cb6c0ec |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:42:43Z |
| publishDate | 2022 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:98c91cf1-6c91-4808-a671-a9b09cb6c0ec2023-05-05T14:22:22ZMitotic DNA synthesis is caused by transcription-replication conflicts in BRCA2-deficient cellsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:98c91cf1-6c91-4808-a671-a9b09cb6c0ecEnglishSymplectic ElementsCell Press2022Groelly, FJDagg, RAPetropoulos, MRossetti, GGPrasad, BPanagopoulos, APaulsen, TKaramichali, AJones, SEOchs, FDionellis, VSPuig Lombardi, EMiossec, MJLockstone, HLegube, GBlackford, ANAltmeyer, MHalazonetis, TDTarsounas, M<p>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 <em>BRCA2</em>-mutated breast tumors. Thus, our work provides a mechanism for how tumor-predisposing <em>BRCA2</em> inactivation links transcription-induced DNA damage with mitotic DNA repair to fuel the genomic instability characteristic of cancer cells.</p> |
| spellingShingle | 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 Mitotic DNA synthesis is caused by transcription-replication conflicts in BRCA2-deficient cells |
| title | Mitotic DNA synthesis is caused by transcription-replication conflicts in BRCA2-deficient cells |
| title_full | Mitotic DNA synthesis is caused by transcription-replication conflicts in BRCA2-deficient cells |
| title_fullStr | Mitotic DNA synthesis is caused by transcription-replication conflicts in BRCA2-deficient cells |
| title_full_unstemmed | Mitotic DNA synthesis is caused by transcription-replication conflicts in BRCA2-deficient cells |
| title_short | Mitotic DNA synthesis is caused by transcription-replication conflicts in BRCA2-deficient cells |
| title_sort | mitotic dna synthesis is caused by transcription replication conflicts in brca2 deficient cells |
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