Mitotic DNA synthesis is caused by transcription-replication conflicts in BRCA2-deficient cells
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...
Gespeichert in:
| Veröffentlicht in: | Molecular cell Jg. 82; H. 18; S. 3382 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Sprache: | Englisch |
| Veröffentlicht: |
United States
15.09.2022
|
| Schlagworte: | |
| ISSN: | 1097-4164, 1097-4164 |
| Online-Zugang: | Weitere Angaben |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| 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. |
|---|---|
| AbstractList | 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.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. 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. |
| Author | Petropoulos, Michalis Panagopoulos, Andreas Paulsen, Teressa Dagg, Rebecca A Ochs, Fena Karamichali, Angeliki Puig Lombardi, Emilia Jones, Samuel E Halazonetis, Thanos D Groelly, Florian J Dionellis, Vasilis S Prasad, Birbal Tarsounas, Madalena Miossec, Matthieu J Rossetti, Giacomo G Lockstone, Helen Blackford, Andrew N Legube, Gaëlle Altmeyer, Matthias |
| Author_xml | – sequence: 1 givenname: Florian J surname: Groelly fullname: Groelly, Florian J organization: Genome Stability and Tumourigenesis Group, Department of Oncology, Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK – sequence: 2 givenname: Rebecca A surname: Dagg fullname: Dagg, Rebecca A organization: Genome Stability and Tumourigenesis Group, Department of Oncology, Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK – sequence: 3 givenname: Michalis surname: Petropoulos fullname: Petropoulos, Michalis organization: Department of Molecular Biology, University of Geneva, 1205 Geneva, Switzerland – sequence: 4 givenname: Giacomo G surname: Rossetti fullname: Rossetti, Giacomo G organization: Department of Molecular Biology, University of Geneva, 1205 Geneva, Switzerland – sequence: 5 givenname: Birbal surname: Prasad fullname: Prasad, Birbal organization: Genome Stability and Tumourigenesis Group, Department of Oncology, Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK – sequence: 6 givenname: Andreas surname: Panagopoulos fullname: Panagopoulos, Andreas organization: Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland – sequence: 7 givenname: Teressa surname: Paulsen fullname: Paulsen, Teressa organization: Genome Stability and Tumourigenesis Group, Department of Oncology, Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK – sequence: 8 givenname: Angeliki surname: Karamichali fullname: Karamichali, Angeliki organization: Department of Molecular Biology, University of Geneva, 1205 Geneva, Switzerland – sequence: 9 givenname: Samuel E surname: Jones fullname: Jones, Samuel E organization: Department of Oncology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK – sequence: 10 givenname: Fena surname: Ochs fullname: Ochs, Fena organization: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK – sequence: 11 givenname: Vasilis S surname: Dionellis fullname: Dionellis, Vasilis S organization: Department of Molecular Biology, University of Geneva, 1205 Geneva, Switzerland – sequence: 12 givenname: Emilia surname: Puig Lombardi fullname: Puig Lombardi, Emilia organization: Genome Stability and Tumourigenesis Group, Department of Oncology, Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK – sequence: 13 givenname: Matthieu J surname: Miossec fullname: Miossec, Matthieu J organization: Bioinformatics and Statistical Genetics Core, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK – sequence: 14 givenname: Helen surname: Lockstone fullname: Lockstone, Helen organization: Bioinformatics and Statistical Genetics Core, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK – sequence: 15 givenname: Gaëlle surname: Legube fullname: Legube, Gaëlle organization: LBCMCP, Centre de Biologie Intégrative (CBI), CNRS, Université de Toulouse, UT3, Toulouse 31062, France – sequence: 16 givenname: Andrew N surname: Blackford fullname: Blackford, Andrew N organization: Department of Oncology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK – sequence: 17 givenname: Matthias surname: Altmeyer fullname: Altmeyer, Matthias organization: Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland – sequence: 18 givenname: Thanos D surname: Halazonetis fullname: Halazonetis, Thanos D email: thanos.halazonetis@unige.ch organization: Department of Molecular Biology, University of Geneva, 1205 Geneva, Switzerland. Electronic address: thanos.halazonetis@unige.ch – sequence: 19 givenname: Madalena surname: Tarsounas fullname: Tarsounas, Madalena email: madalena.tarsounas@oncology.ox.ac.uk organization: Genome Stability and Tumourigenesis Group, Department of Oncology, Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK. Electronic address: madalena.tarsounas@oncology.ox.ac.uk |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/36002001$$D View this record in MEDLINE/PubMed |
| BookMark | eNpNUE1LxDAUDLLifug_EMnRS2uSJk17XNdPWBVEzyVNXjBLm9YmPey_t4srCA9mBuYNwyzRzHceELqkJKWE5je7tO0aDU3KCGMpkSmh9AQtKCllwmnOZ__4HC1D2BFCuSjKMzTPckLYJBeoenGxi07ju9c1DnsfvyC4gKfTagxgcL3HcVA-6MH10XU-GaBvnFYHjnXn7STi9ODx7ftmzRID1mkHPuKpWxPO0alVTYCLI67Q58P9x-Yp2b49Pm_W20SLMo-JJpnJlC7KuihzyokwANSArIFzASYTTFOrClDWMmtkTQpOhTZCmaygwmq2Qte_uf3QfY8QYtW6cGigPHRjqJgkuaRCTkkrdHW0jnULpuoH16phX_2Nwn4A9qdotw |
| CitedBy_id | crossref_primary_10_1016_j_jmb_2023_168294 crossref_primary_10_1038_s41467_023_40779_9 crossref_primary_10_1093_nar_gkae546 crossref_primary_10_1146_annurev_genet_080320_031523 crossref_primary_10_1042_BST20241633 crossref_primary_10_3390_ijms231911331 crossref_primary_10_1016_j_dnarep_2023_103548 crossref_primary_10_1038_s41467_024_53917_8 crossref_primary_10_1038_s42003_022_04360_2 crossref_primary_10_1016_j_canlet_2024_217359 crossref_primary_10_1038_s44318_024_00169_3 crossref_primary_10_1016_j_molcel_2023_08_023 crossref_primary_10_1016_j_dnarep_2025_103872 crossref_primary_10_1016_j_celrep_2025_115259 crossref_primary_10_1172_JCI172137 crossref_primary_10_1016_j_molcel_2023_11_036 crossref_primary_10_3390_biology12050671 crossref_primary_10_1158_0008_5472_CAN_23_3603 crossref_primary_10_1038_s41586_024_07217_2 crossref_primary_10_1016_j_molcel_2024_07_004 crossref_primary_10_1172_JCI173718 crossref_primary_10_1038_s41467_023_40243_8 crossref_primary_10_1093_nar_gkaf109 crossref_primary_10_1016_j_molcel_2022_08_026 crossref_primary_10_1126_sciadv_adt8346 crossref_primary_10_1158_0008_5472_CAN_24_2225 crossref_primary_10_1016_j_ceb_2024_102448 crossref_primary_10_1016_j_tig_2025_05_010 crossref_primary_10_1016_j_mrrev_2023_108475 crossref_primary_10_1016_j_semcancer_2024_02_002 crossref_primary_10_1016_j_molcel_2023_08_018 crossref_primary_10_1038_s41467_024_52507_y crossref_primary_10_1186_s12943_024_02000_3 |
| ContentType | Journal Article |
| Copyright | Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved. |
| Copyright_xml | – notice: Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved. |
| DBID | CGR CUY CVF ECM EIF NPM 7X8 |
| DOI | 10.1016/j.molcel.2022.07.011 |
| DatabaseName | Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed MEDLINE - Academic |
| DatabaseTitle | MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) MEDLINE - Academic |
| DatabaseTitleList | MEDLINE - Academic MEDLINE |
| Database_xml | – sequence: 1 dbid: NPM name: PubMed url: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: 7X8 name: MEDLINE - Academic url: https://search.proquest.com/medline sourceTypes: Aggregation Database |
| DeliveryMethod | no_fulltext_linktorsrc |
| Discipline | Biology |
| EISSN | 1097-4164 |
| ExternalDocumentID | 36002001 |
| Genre | Research Support, Non-U.S. Gov't Journal Article |
| GrantInformation_xml | – fundername: Cancer Research UK grantid: C29215/A20772 – fundername: Cancer Research UK grantid: 20772 – fundername: Wellcome Trust grantid: 203141/Z/16/Z – fundername: Cancer Research UK grantid: DRCPGM\100001 |
| GroupedDBID | --- --K -DZ -~X 0R~ 123 1~5 2WC 4.4 457 4G. 5RE 62- 7-5 AAEDT AAEDW AAHBH AAKRW AAKUH AALRI AAMRU AAVLU AAXUO AAYWO ABDGV ABJNI ABMAC ACGFO ACGFS ACNCT ACVFH ADBBV ADCNI ADEZE ADVLN AEFWE AENEX AEUPX AEXQZ AFFNX AFPUW AFTJW AGCQF AGKMS AIGII AITUG AKAPO AKBMS AKRWK AKYEP ALMA_UNASSIGNED_HOLDINGS AMRAJ APXCP ASPBG AVWKF AZFZN BAWUL CGR CS3 CUY CVF DIK DU5 E3Z EBS ECM EFKBS EIF F5P FCP FDB FEDTE FIRID HH5 HVGLF IH2 IHE IXB J1W JIG KQ8 L7B M3Z M41 N9A NPM O-L O9- OK1 P2P ROL RPZ SDG SES SSZ TR2 7X8 |
| ID | FETCH-LOGICAL-c596t-c03d3ac89b8961405dee1de7be445ed352c1fa8eaff2fd7b08415cd5ad3815fc2 |
| IEDL.DBID | 7X8 |
| ISICitedReferencesCount | 38 |
| ISICitedReferencesURI | http://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestLinkType=CitingArticles&DestApp=WOS_CPL&KeyUT=000861183500008&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| ISSN | 1097-4164 |
| IngestDate | Thu Oct 02 12:02:58 EDT 2025 Mon Jul 21 06:07:54 EDT 2025 |
| IsDoiOpenAccess | false |
| IsOpenAccess | true |
| IsPeerReviewed | true |
| IsScholarly | true |
| Issue | 18 |
| Keywords | genome stability transcription-replication conflicts MiDAS TRCs R-loops mitotic DNA synthesis BRCA2 |
| Language | English |
| License | Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved. |
| LinkModel | DirectLink |
| MergedId | FETCHMERGED-LOGICAL-c596t-c03d3ac89b8961405dee1de7be445ed352c1fa8eaff2fd7b08415cd5ad3815fc2 |
| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| OpenAccessLink | http://www.cell.com/article/S1097276522007079/pdf |
| PMID | 36002001 |
| PQID | 2706715735 |
| PQPubID | 23479 |
| ParticipantIDs | proquest_miscellaneous_2706715735 pubmed_primary_36002001 |
| PublicationCentury | 2000 |
| PublicationDate | 2022-09-15 |
| PublicationDateYYYYMMDD | 2022-09-15 |
| PublicationDate_xml | – month: 09 year: 2022 text: 2022-09-15 day: 15 |
| PublicationDecade | 2020 |
| PublicationPlace | United States |
| PublicationPlace_xml | – name: United States |
| PublicationTitle | Molecular cell |
| PublicationTitleAlternate | Mol Cell |
| PublicationYear | 2022 |
| SSID | ssj0014589 |
| Score | 2.5634515 |
| Snippet | Aberrant replication causes cells lacking BRCA2 to enter mitosis with under-replicated DNA, which activates a repair mechanism known as mitotic DNA synthesis... |
| SourceID | proquest pubmed |
| SourceType | Aggregation Database Index Database |
| StartPage | 3382 |
| SubjectTerms | Aphidicolin - pharmacology BRCA2 Protein - genetics Chromosome Fragile Sites - genetics DNA - genetics DNA Damage DNA Replication Genomic Instability Humans Mitosis - genetics |
| Title | Mitotic DNA synthesis is caused by transcription-replication conflicts in BRCA2-deficient cells |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/36002001 https://www.proquest.com/docview/2706715735 |
| Volume | 82 |
| WOSCitedRecordID | wos000861183500008&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| hasFullText | |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| link | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV1LSwMxEA5qFbz4ftQXEbwGu9nE7J6kVouXliIKvS15TKCg29pthf57J7tbexIEYcllCYSZycyXfJMZQm48pGCs80wIJZhwwJkxXDEbSq87PMppI8pmE6rfT4bDdFBfuBV1WuXSJ5aO2o1tuCO_5Qr9aiRVLO8nnyx0jQrsat1CY500YoQywarVcMUiCFm2wAskK0PgIZZP58r8ro_xu4VAPnBelu-Mot9BZhlsurv_XeYe2alhJm1XdrFP1iA_IFtV48nFIcl6uJHxF33st2mxyBEFFqOC4mf1vABHzYLOQhRb-hQ2hR-im9r6KQlOyOnDS6fNmYNQiQIDGA1MQHFE3rpPr51nVrdaQKWkdzNmW7GLtU1Sk6QYsFvSAUQOlAEhJDhEaTbyOgHtPfdOmVaCgd86qR1GfOktPyYb-TiHU0IR4sgINNeBK1YmMVL4BPDYwlMhtJdNcr2UXIamHFalcxjPi2wluyY5qcSfTaqaG1kc-ENU6dkfZp-T7aDVkNURyQvS8LiR4ZJs2q_ZqJhelTaCY3_Q-wb50cgK |
| linkProvider | ProQuest |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Mitotic+DNA+synthesis+is+caused+by+transcription-replication+conflicts+in+BRCA2-deficient+cells&rft.jtitle=Molecular+cell&rft.au=Groelly%2C+Florian+J&rft.au=Dagg%2C+Rebecca+A&rft.au=Petropoulos%2C+Michalis&rft.au=Rossetti%2C+Giacomo+G&rft.date=2022-09-15&rft.issn=1097-4164&rft.eissn=1097-4164&rft.volume=82&rft.issue=18&rft.spage=3382&rft_id=info:doi/10.1016%2Fj.molcel.2022.07.011&rft.externalDBID=NO_FULL_TEXT |
| thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=1097-4164&client=summon |
| thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=1097-4164&client=summon |
| thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=1097-4164&client=summon |