Hyper-recombination in ribosomal DNA is driven by long-range resection-independent RAD51 accumulation

Zita Gál, Stavroula Boukoura, Kezia Catharina Oxe, Sara Badawi, Blanca Nieto, Lea Milling Korsholm, Sille Blangstrup Geisler, Ekaterina Dulina, Anna Vestergaard Rasmussen, Christina Dahl, Wei Lv, Huixin Xu, Xiaoguang Pan, Stefanos Arampatzis, Danai-Eleni Stratou, Panagiotis Galanos, Lin Lin, Per Guldberg, Jiri Bartek, Yonglun Luo and Dorthe H. Larsen ()
Additional contact information
Zita Gál: Danish Cancer Institute
Stavroula Boukoura: Danish Cancer Institute
Kezia Catharina Oxe: Danish Cancer Institute
Sara Badawi: Danish Cancer Institute
Blanca Nieto: Danish Cancer Institute
Lea Milling Korsholm: Danish Cancer Institute
Sille Blangstrup Geisler: Danish Cancer Institute
Ekaterina Dulina: Danish Cancer Institute
Anna Vestergaard Rasmussen: Danish Cancer Institute
Christina Dahl: Danish Cancer Institute
Wei Lv: Aarhus University
Huixin Xu: Aarhus University
Xiaoguang Pan: University of Copenhagen
Stefanos Arampatzis: Danish Cancer Institute
Danai-Eleni Stratou: Danish Cancer Institute
Panagiotis Galanos: Danish Cancer Institute
Lin Lin: Aarhus University
Per Guldberg: Danish Cancer Institute
Jiri Bartek: Danish Cancer Institute
Yonglun Luo: Aarhus University
Dorthe H. Larsen: Danish Cancer Institute

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-52189-6

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