Hyper-recombination in ribosomal DNA is driven by long-range resection-independent RAD51 accumulation
Year: 2024
Type: article
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. Ribosomal DNA is an unstable genomic region with the underlying mechanisms remaining elusive. Here the authors find that rDNA hyper recombination in Bloom Syndrome cells arises from RAD51 accumulation in the absence of long-range resection and cause genome instability through micronuclei formation.
Source: Nature Communications
Authors: 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, Dorthe H. Larsen
Institutions: University of Copenhagen, Novo Nordisk Foundation, Copenhagen University Hospital, Rigshospitalet, Aarhus University, University of Southern Denmark, Aarhus University Hospital, Steno Diabetes Center Aarhus, Science for Life Laboratory, Karolinska Institutet, BGI Group (China), BGI Research
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,790
Awards: G1061232576, G1328519016, Mechanisms maintaining ribosomal DNA integrity and their role in cancer, G2001053284, G2026332892, G2206752652, G434337789, G4395847220, G4453710320, G4486413229, G4488819273, G5658930707, G6555502746, Intelligent and Artificial Designer Cells & Organs for Regenerative Transplant Medicine (iART), G7773570351, G7968616192, Circular DNA in diagnosis and disease models, G8337539906, G8471132896, G8642073213
OpenAlex ID: W4402312326