Hyper-recombination in ribosomal DNA is driven by long-range resection-independent RAD51 accumulation
Ribosomal DNA (rDNA) encodes the ribosomal RNA genes and represents an intrinsically unstable genomic region. However, the underlying mechanisms and implications for genome integrity remain elusive. Here, we use Bloom syndrome (BS), a rare genetic disease characterized by DNA repair defects and hyper-unstable rDNA, as a model to investigate the mechanisms leading to rDNA instability. We find that in Bloom helicase (BLM) proficient cells, the homologous recombination (HR) pathway in rDNA resembles that in nuclear chromatin; it is initiated by resection, replication protein A (RPA) loading and BRCA2-dependent RAD51 filament formation. However, BLM deficiency compromises RPA-loading and BRCA1/2 recruitment to rDNA, but not RAD51 accumulation. RAD51 accumulates at rDNA despite depletion of long-range resection nucleases and rDNA damage results in micronuclei when BLM is absent. In summary, our findings indicate that rDNA is permissive to RAD51 accumulation in the absence of BLM, leading to micronucleation and potentially global genomic instability.
Authors
- Stefanos Arampatzis (ORCID: https://orcid.org/0009-0004-2393-4575)
- Blanca Nieto (ORCID: https://orcid.org/0000-0001-9923-8534)
- Huixin Xu
- Kezia Catharina Oxe (ORCID: https://orcid.org/0000-0002-4921-4750)
- Christina Dahl (ORCID: https://orcid.org/0000-0002-6177-2640)
- Anna Vestergaard Rasmussen
- Stavroula Boukoura (ORCID: https://orcid.org/0000-0002-7176-103X)
- Yonglun Luo (ORCID: https://orcid.org/0000-0002-0007-7759)
- Lea Milling Korsholm (ORCID: https://orcid.org/0009-0007-9632-8957)
- Per Guldberg (ORCID: https://orcid.org/0000-0002-4424-4803)
- Dorthe Helena Larsen (ORCID: https://orcid.org/0000-0002-8280-1252)
- Wei Zhong Lv (ORCID: https://orcid.org/0000-0003-0874-3477)
- Xiaoguang Pan (ORCID: https://orcid.org/0000-0002-2688-9245)
- Zita Gál (ORCID: https://orcid.org/0000-0002-2805-4356)
- Ekaterina Dulina
- Panagiotis Galanos (ORCID: https://orcid.org/0000-0003-1403-4685)
- Jiří Bártek (ORCID: https://orcid.org/0000-0003-2013-7525)
- Lin Lin (ORCID: https://orcid.org/0000-0002-7546-4948)
- Danai-Eleni Stratou (ORCID: https://orcid.org/0009-0002-7380-5152)
- Sara A. Badawi
- Sille Blangstrup Geisler
Institutions
- University of Copenhagen (DK)
- University of Southern Denmark (DK)
- Aarhus University (DK)
- Science for Life Laboratory (SE)
- Novo Nordisk Foundation (DK)
- Aarhus University Hospital (DK)
- Copenhagen University Hospital (DK)
- Rigshospitalet (DK)
- Karolinska Institutet (SE)
- Danish Cancer Society (DK)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-06
- DOI
- https://doi.org/10.1038/s41467-024-52189-6
- Citations
- 8
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 1.64
Funders
- Kræftens Bekæmpelse
- European Commission
- Lundbeckfonden
- Novo Nordisk
- Vetenskapsrådet
- Danmarks Frie Forskningsfond
- Novo Nordisk Fonden
- H. Lundbeck A/S
- Horizon 2020 Framework Programme