The homologous recombination factors BRCA2 and PALB2 interplay with mismatch repair pathways to maintain centromere stability and cell viability
Summary: Centromeres are crucial for chromosome segregation but are vulnerable to breakage and recombination due to their repetitive DNA. The mechanisms protecting centromeres from these instabilities remain incompletely understood. This study investigates the role of the homologous recombination (H...
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Elsevier
2025-02-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725000300 |
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| author | Emily Graham Lucia Rampazzo Chin Wei Brian Leung Jacob Wall Emőke Zsanett Gerőcz Mikhail Liskovykh Nikolay Goncharov Xanita Saayman Ramazan Gundogdu Masato T. Kanemaki Hiroshi Masumoto Vladimir Larionov Natalay Kouprina Fumiko Esashi |
| author_facet | Emily Graham Lucia Rampazzo Chin Wei Brian Leung Jacob Wall Emőke Zsanett Gerőcz Mikhail Liskovykh Nikolay Goncharov Xanita Saayman Ramazan Gundogdu Masato T. Kanemaki Hiroshi Masumoto Vladimir Larionov Natalay Kouprina Fumiko Esashi |
| author_sort | Emily Graham |
| collection | DOAJ |
| description | Summary: Centromeres are crucial for chromosome segregation but are vulnerable to breakage and recombination due to their repetitive DNA. The mechanisms protecting centromeres from these instabilities remain incompletely understood. This study investigates the role of the homologous recombination (HR) mediators BRCA2 and PALB2 in centromere stability. We find that BRCA2, but not PALB2, is essential for maintaining a human artificial chromosome. In native chromosomes, BRCA2 ensures CENP-A occupancy and prevents DNA fragility at centromeres. Conversely, PALB2 does not affect CENP-A, whereas its depletion increases centromeric DNA breaks in non-cancerous cells only. Interestingly, depleting the mismatch repair (MMR) factor MLH1 masks centromere fragility caused by BRCA2 or PALB2 loss, suggesting that MLH1 contributes to DNA instability when BRCA2 or PALB2 is absent. However, cells deficient in both BRCA2/PALB2 and MLH1 have reduced survival. These results highlight a critical balance between HR and MMR factors in preserving centromere integrity and cell viability. |
| format | Article |
| id | doaj-art-c606bb9a23964692ba388280de3c28e2 |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-c606bb9a23964692ba388280de3c28e22025-02-02T05:27:06ZengElsevierCell Reports2211-12472025-02-01442115259The homologous recombination factors BRCA2 and PALB2 interplay with mismatch repair pathways to maintain centromere stability and cell viabilityEmily Graham0Lucia Rampazzo1Chin Wei Brian Leung2Jacob Wall3Emőke Zsanett Gerőcz4Mikhail Liskovykh5Nikolay Goncharov6Xanita Saayman7Ramazan Gundogdu8Masato T. Kanemaki9Hiroshi Masumoto10Vladimir Larionov11Natalay Kouprina12Fumiko Esashi13Sir William Dunn School of Pathology, University of Oxford, Oxford, UKSir William Dunn School of Pathology, University of Oxford, Oxford, UKSir William Dunn School of Pathology, University of Oxford, Oxford, UKSir William Dunn School of Pathology, University of Oxford, Oxford, UKSir William Dunn School of Pathology, University of Oxford, Oxford, UKDevelopmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USADevelopmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USASir William Dunn School of Pathology, University of Oxford, Oxford, UKSir William Dunn School of Pathology, University of Oxford, Oxford, UK; Department of Pharmacy Services, Vocational School of Health Services, Bingol University, Bingol, TürkiyeDepartment of Chromosome Science, National Institute of Genetics, Research Organization of Information and Systems (ROIS), Shizuoka, Japan; Department of Advanced Studies, SOKENDAI, Shizuoka, Japan; Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, JapanLaboratory of Chromosome Engineering, Department of Frontier Research and Development, Kazusa DNA Research Institute, Kisarazu, Chiba 292-0818d, JapanDevelopmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USADevelopmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USASir William Dunn School of Pathology, University of Oxford, Oxford, UK; Corresponding authorSummary: Centromeres are crucial for chromosome segregation but are vulnerable to breakage and recombination due to their repetitive DNA. The mechanisms protecting centromeres from these instabilities remain incompletely understood. This study investigates the role of the homologous recombination (HR) mediators BRCA2 and PALB2 in centromere stability. We find that BRCA2, but not PALB2, is essential for maintaining a human artificial chromosome. In native chromosomes, BRCA2 ensures CENP-A occupancy and prevents DNA fragility at centromeres. Conversely, PALB2 does not affect CENP-A, whereas its depletion increases centromeric DNA breaks in non-cancerous cells only. Interestingly, depleting the mismatch repair (MMR) factor MLH1 masks centromere fragility caused by BRCA2 or PALB2 loss, suggesting that MLH1 contributes to DNA instability when BRCA2 or PALB2 is absent. However, cells deficient in both BRCA2/PALB2 and MLH1 have reduced survival. These results highlight a critical balance between HR and MMR factors in preserving centromere integrity and cell viability.http://www.sciencedirect.com/science/article/pii/S2211124725000300CP: Molecular biology |
| spellingShingle | Emily Graham Lucia Rampazzo Chin Wei Brian Leung Jacob Wall Emőke Zsanett Gerőcz Mikhail Liskovykh Nikolay Goncharov Xanita Saayman Ramazan Gundogdu Masato T. Kanemaki Hiroshi Masumoto Vladimir Larionov Natalay Kouprina Fumiko Esashi The homologous recombination factors BRCA2 and PALB2 interplay with mismatch repair pathways to maintain centromere stability and cell viability Cell Reports CP: Molecular biology |
| title | The homologous recombination factors BRCA2 and PALB2 interplay with mismatch repair pathways to maintain centromere stability and cell viability |
| title_full | The homologous recombination factors BRCA2 and PALB2 interplay with mismatch repair pathways to maintain centromere stability and cell viability |
| title_fullStr | The homologous recombination factors BRCA2 and PALB2 interplay with mismatch repair pathways to maintain centromere stability and cell viability |
| title_full_unstemmed | The homologous recombination factors BRCA2 and PALB2 interplay with mismatch repair pathways to maintain centromere stability and cell viability |
| title_short | The homologous recombination factors BRCA2 and PALB2 interplay with mismatch repair pathways to maintain centromere stability and cell viability |
| title_sort | homologous recombination factors brca2 and palb2 interplay with mismatch repair pathways to maintain centromere stability and cell viability |
| topic | CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725000300 |
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