Graham Emily, Rampazzo Lucia, Leung Chin Wei Brian, Wall Jacob, Gerőcz Emőke Zsanett, Liskovykh Mikhail, Goncharov Nikolay, Saayman Xanita, Gundogdu Ramazan, Kanemaki Masato T, Masumoto Hiroshi, Larionov Vladimir, Kouprina Natalay, Esashi Fumiko
Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Cell Rep. 2025 Feb 25;44(2):115259. doi: 10.1016/j.celrep.2025.115259. Epub 2025 Jan 31.
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.
着丝粒对于染色体分离至关重要，但由于其重复DNA，容易发生断裂和重组。保护着丝粒免受这些不稳定性影响的机制仍未完全了解。本研究调查了同源重组（HR）介导因子BRCA2和PALB2在着丝粒稳定性中的作用。我们发现，BRCA2而非PALB2对于维持人工染色体至关重要。在天然染色体中，BRCA2确保着丝粒蛋白A（CENP - A）的占据，并防止着丝粒处的DNA脆弱性。相反，PALB2不影响CENP - A，而其缺失仅在非癌细胞中增加着丝粒DNA断裂。有趣的是，缺失错配修复（MMR）因子MLH1会掩盖由BRCA2或PALB2缺失引起的着丝粒脆弱性，这表明当BRCA2或PALB2缺失时，MLH1会导致DNA不稳定。然而，同时缺乏BRCA2/PALB2和MLH1的细胞存活率降低。这些结果突出了HR和MMR因子在维持着丝粒完整性和细胞活力方面的关键平衡。
