Specialized replication mechanisms maintain genome stability at human centromeres
The high incidence of whole-arm chromosome aneuploidy and translocations in tumors suggests instability of centromeres, unique loci built on repetitive sequences and essential for chromosome separation. The causes behind this fragility and the mechanisms preserving centromere integrity remain elusiv...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Cell Press
2024
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| _version_ | 1824459310388740096 |
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| author | Scelfo, A Angrisani, A Grillo, M Barnes, BM Muyas, F Sauer, CM Leung, CWB Dumont, M Grison, M Mazaud, D Garnier, M Guintini, L Nelson, L Esashi, F Cortés-Ciriano, I Taylor, SS Déjardin, J Wilhelm, T Fachinetti, D |
| author_facet | Scelfo, A Angrisani, A Grillo, M Barnes, BM Muyas, F Sauer, CM Leung, CWB Dumont, M Grison, M Mazaud, D Garnier, M Guintini, L Nelson, L Esashi, F Cortés-Ciriano, I Taylor, SS Déjardin, J Wilhelm, T Fachinetti, D |
| author_sort | Scelfo, A |
| collection | OXFORD |
| description | The high incidence of whole-arm chromosome aneuploidy and translocations in tumors suggests instability of centromeres, unique loci built on repetitive sequences and essential for chromosome separation. The causes behind this fragility and the mechanisms preserving centromere integrity remain elusive. We show that replication stress, hallmark of pre-cancerous lesions, promotes centromeric breakage in mitosis, due to spindle forces and endonuclease activities. Mechanistically, we unveil unique dynamics of the centromeric replisome distinct from the rest of the genome. Locus-specific proteomics identifies specialized DNA replication and repair proteins at centromeres, highlighting them as difficult-to-replicate regions. The translesion synthesis pathway, along with other factors, acts to sustain centromere replication and integrity. Prolonged stress causes centromeric alterations like ruptures and translocations, as observed in ovarian cancer models experiencing replication stress. This study provides unprecedented insights into centromere replication and integrity, proposing mechanistic insights into the origins of centromere alterations leading to abnormal cancerous karyotypes. |
| first_indexed | 2024-03-07T08:26:21Z |
| format | Journal article |
| id | oxford-uuid:88254a89-75c2-40ad-9cd2-b328e448e9e3 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2025-02-19T04:39:45Z |
| publishDate | 2024 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:88254a89-75c2-40ad-9cd2-b328e448e9e32025-02-14T10:16:24ZSpecialized replication mechanisms maintain genome stability at human centromeresJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:88254a89-75c2-40ad-9cd2-b328e448e9e3EnglishSymplectic ElementsCell Press2024Scelfo, AAngrisani, AGrillo, MBarnes, BMMuyas, FSauer, CMLeung, CWBDumont, MGrison, MMazaud, DGarnier, MGuintini, LNelson, LEsashi, FCortés-Ciriano, ITaylor, SSDéjardin, JWilhelm, TFachinetti, DThe high incidence of whole-arm chromosome aneuploidy and translocations in tumors suggests instability of centromeres, unique loci built on repetitive sequences and essential for chromosome separation. The causes behind this fragility and the mechanisms preserving centromere integrity remain elusive. We show that replication stress, hallmark of pre-cancerous lesions, promotes centromeric breakage in mitosis, due to spindle forces and endonuclease activities. Mechanistically, we unveil unique dynamics of the centromeric replisome distinct from the rest of the genome. Locus-specific proteomics identifies specialized DNA replication and repair proteins at centromeres, highlighting them as difficult-to-replicate regions. The translesion synthesis pathway, along with other factors, acts to sustain centromere replication and integrity. Prolonged stress causes centromeric alterations like ruptures and translocations, as observed in ovarian cancer models experiencing replication stress. This study provides unprecedented insights into centromere replication and integrity, proposing mechanistic insights into the origins of centromere alterations leading to abnormal cancerous karyotypes. |
| spellingShingle | Scelfo, A Angrisani, A Grillo, M Barnes, BM Muyas, F Sauer, CM Leung, CWB Dumont, M Grison, M Mazaud, D Garnier, M Guintini, L Nelson, L Esashi, F Cortés-Ciriano, I Taylor, SS Déjardin, J Wilhelm, T Fachinetti, D Specialized replication mechanisms maintain genome stability at human centromeres |
| title | Specialized replication mechanisms maintain genome stability at human centromeres |
| title_full | Specialized replication mechanisms maintain genome stability at human centromeres |
| title_fullStr | Specialized replication mechanisms maintain genome stability at human centromeres |
| title_full_unstemmed | Specialized replication mechanisms maintain genome stability at human centromeres |
| title_short | Specialized replication mechanisms maintain genome stability at human centromeres |
| title_sort | specialized replication mechanisms maintain genome stability at human centromeres |
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