Journal article
The homologous recombination factors BRCA2 and PALB2 interplay with mismatch repair pathways to maintain centromere stability and cell viability
- Abstract:
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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- Files:
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(Preview, Version of record, pdf, 22.1MB, Terms of use)
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- Publisher copy:
- 10.1016/j.celrep.2025.115259
Authors
+ Medical Research Council
More from this funder
- Funder identifier:
- https://ror.org/03x94j517
- Funding agency for:
- Graham, E
- Grant:
- 18/19_MSD_2111222
- Programme:
- Medical Sciences Graduate School studentship
+ Biotechnology and Biological Sciences Research Council
More from this funder
- Funder identifier:
- https://ror.org/00cwqg982
- Funding agency for:
- Rampazzo, L
- Grant:
- BB/M011224/1
- Programme:
- Project 175778
+ Wellcome Trust
More from this funder
- Funder identifier:
- https://ror.org/029chgv08
- Funding agency for:
- Esashi, F
- Grant:
- 101009/Z/13/Z
- Programme:
- Wellcome Trust Senior Research Fellowships in Basic Biomedical Science
+ Japan Science and Technology Agency
More from this funder
- Funder identifier:
- https://ror.org/00097mb19
- Funding agency for:
- Kanemaki, MT
- Grant:
- JPMJCR21E6
+ Japan Society for the Promotion of Science
More from this funder
- Funder identifier:
- https://ror.org/00hhkn466
- Funding agency for:
- Kanemaki, MT
- Grant:
- JP23H04925
- JP21H04719
- Publisher:
- Cell Press
- Journal:
- Cell Reports More from this journal
- Volume:
- 44
- Issue:
- 2
- Article number:
- 115259
- Place of publication:
- United States
- Publication date:
- 2025-01-31
- Acceptance date:
- 2025-01-13
- DOI:
- EISSN:
-
2211-1247
- ISSN:
-
2639-1856
- Pmid:
-
39893637
- Language:
-
English
- Keywords:
- Pubs id:
-
2083850
- Local pid:
-
pubs:2083850
- Deposit date:
-
2025-02-20
- ARK identifier:
Terms of use
- Copyright holder:
- Graham et al.
- Copyright date:
- 2025
- Rights statement:
- © 2025 The Authors. Published by Elsevier Inc. This is an open access article under a Creative Commons license.
- Licence:
- CC Attribution (CC BY)
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