Genomic context influences translesion synthesis DNA polymerase-dependent mechanisms of micronuclei induction by G-quadruplexes
Summary: Guanine quadruplexes (G4s) are non-canonical DNA structures that can trigger micronuclei (MNi). Mechanisms of micronuclei formation by G4s are not fully understood. Here, we show that G4 stabilization can trigger cell-cycle-phase-specific mechanisms of replication fork stalling and DNA synt...
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Elsevier
2025-05-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725004772 |
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| author | Simona Pepe Federico Guerra Marco Russo Renée C. Duardo Giovanni Capranico |
| author_facet | Simona Pepe Federico Guerra Marco Russo Renée C. Duardo Giovanni Capranico |
| author_sort | Simona Pepe |
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| description | Summary: Guanine quadruplexes (G4s) are non-canonical DNA structures that can trigger micronuclei (MNi). Mechanisms of micronuclei formation by G4s are not fully understood. Here, we show that G4 stabilization can trigger cell-cycle-phase-specific mechanisms of replication fork stalling and DNA synthesis restart dependent on translesion synthesis (TLS) DNA polymerases (Pols). Fork stalling is caused by G-loops and high transcription during early S only. Moreover, while induction of micronuclei is dependent on DNA Pol η throughout S phase, primase and DNA-directed polymerase (PrimPol) is required in late S only. DNA breakage is not an immediate response to stabilized G4s but rather a consequence of persistent G4-mediated replication stress. Thus, different modes of fork stalling and restart, based on genomic context and TLS Pols, avoid immediate DNA breakage at stalled forks but at the expense of a risk of later mitotic chromosomal instability. The insights can lead to the development of more effective therapies for cancer and neurological diseases. |
| format | Article |
| id | doaj-art-b56bba16ac42491992d421ac14f641c2 |
| institution | OA Journals |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
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| series | Cell Reports |
| spelling | doaj-art-b56bba16ac42491992d421ac14f641c22025-08-20T01:49:46ZengElsevierCell Reports2211-12472025-05-0144511570610.1016/j.celrep.2025.115706Genomic context influences translesion synthesis DNA polymerase-dependent mechanisms of micronuclei induction by G-quadruplexesSimona Pepe0Federico Guerra1Marco Russo2Renée C. Duardo3Giovanni Capranico4Department of Pharmacy and Biotechnology, University of Bologna, Bologna, ItalyDepartment of Pharmacy and Biotechnology, University of Bologna, Bologna, ItalyDepartment of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy; Preclinical & Translational Research in Oncology (PRO), IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, ItalyDepartment of Pharmacy and Biotechnology, University of Bologna, Bologna, ItalyDepartment of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy; Preclinical & Translational Research in Oncology (PRO), IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Corresponding authorSummary: Guanine quadruplexes (G4s) are non-canonical DNA structures that can trigger micronuclei (MNi). Mechanisms of micronuclei formation by G4s are not fully understood. Here, we show that G4 stabilization can trigger cell-cycle-phase-specific mechanisms of replication fork stalling and DNA synthesis restart dependent on translesion synthesis (TLS) DNA polymerases (Pols). Fork stalling is caused by G-loops and high transcription during early S only. Moreover, while induction of micronuclei is dependent on DNA Pol η throughout S phase, primase and DNA-directed polymerase (PrimPol) is required in late S only. DNA breakage is not an immediate response to stabilized G4s but rather a consequence of persistent G4-mediated replication stress. Thus, different modes of fork stalling and restart, based on genomic context and TLS Pols, avoid immediate DNA breakage at stalled forks but at the expense of a risk of later mitotic chromosomal instability. The insights can lead to the development of more effective therapies for cancer and neurological diseases.http://www.sciencedirect.com/science/article/pii/S2211124725004772CP: Molecular biology |
| spellingShingle | Simona Pepe Federico Guerra Marco Russo Renée C. Duardo Giovanni Capranico Genomic context influences translesion synthesis DNA polymerase-dependent mechanisms of micronuclei induction by G-quadruplexes Cell Reports CP: Molecular biology |
| title | Genomic context influences translesion synthesis DNA polymerase-dependent mechanisms of micronuclei induction by G-quadruplexes |
| title_full | Genomic context influences translesion synthesis DNA polymerase-dependent mechanisms of micronuclei induction by G-quadruplexes |
| title_fullStr | Genomic context influences translesion synthesis DNA polymerase-dependent mechanisms of micronuclei induction by G-quadruplexes |
| title_full_unstemmed | Genomic context influences translesion synthesis DNA polymerase-dependent mechanisms of micronuclei induction by G-quadruplexes |
| title_short | Genomic context influences translesion synthesis DNA polymerase-dependent mechanisms of micronuclei induction by G-quadruplexes |
| title_sort | genomic context influences translesion synthesis dna polymerase dependent mechanisms of micronuclei induction by g quadruplexes |
| topic | CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725004772 |
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