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; Dorthe H Larsen

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 LuoDorthe H Larsen^*

^*Corresponding author for this work

Department of Genomic Medicine

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.

Original language	English
Article number	7797
Journal	Nature Communications
Volume	15
Issue number	1
Pages (from-to)	7797
ISSN	2041-1722
Publication status	Published - 6 Sept 2024

Keywords

Rad51 Recombinase/metabolism
DNA, Ribosomal/genetics
Humans
RecQ Helicases/metabolism
Genomic Instability
Replication Protein A/metabolism
Homologous Recombination
Bloom Syndrome/genetics
BRCA2 Protein/metabolism
BRCA1 Protein/metabolism
DNA Repair

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https://www.nature.com/articles/s41467-024-52189-6Licence: CC BY-NC-ND

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Gál, Z., Boukoura, S., Oxe, K. C., Badawi, S., Nieto, B., Korsholm, L. M., Geisler, S. B., Dulina, E., Rasmussen, A. V., Dahl, C., Lv, W., Xu, H., Pan, X., Arampatzis, S., Stratou, D.-E., Galanos, P., Lin, L., Guldberg, P., Bartek, J., ... Larsen, D. H. (2024). Hyper-recombination in ribosomal DNA is driven by long-range resection-independent RAD51 accumulation. Nature Communications, 15(1), 7797. Article 7797. https://www.nature.com/articles/s41467-024-52189-6

Gál, Z, Boukoura, S, Oxe, KC, Badawi, S, Nieto, B, Korsholm, LM, Geisler, SB, Dulina, E, Rasmussen, AV, Dahl, C, Lv, W, Xu, H, Pan, X, Arampatzis, S, Stratou, D-E, Galanos, P, Lin, L, Guldberg, P, Bartek, J, Luo, Y & Larsen, DH 2024, 'Hyper-recombination in ribosomal DNA is driven by long-range resection-independent RAD51 accumulation', Nature Communications, vol. 15, no. 1, 7797, pp. 7797. <https://www.nature.com/articles/s41467-024-52189-6>

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title = "Hyper-recombination in ribosomal DNA is driven by long-range resection-independent RAD51 accumulation",

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.",

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author = "Zita G{\'a}l and Stavroula Boukoura and Oxe, {Kezia Catharina} and Sara Badawi and Blanca Nieto and Korsholm, {Lea Milling} and Geisler, {Sille Blangstrup} and Ekaterina Dulina and Rasmussen, {Anna Vestergaard} and Christina Dahl and Wei Lv and Huixin Xu and Xiaoguang Pan and Stefanos Arampatzis and Danai-Eleni Stratou and Panagiotis Galanos and Lin Lin and Per Guldberg and Jiri Bartek and Yonglun Luo and Larsen, {Dorthe H}",

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T1 - Hyper-recombination in ribosomal DNA is driven by long-range resection-independent RAD51 accumulation

AU - Gál, Zita

AU - Boukoura, Stavroula

AU - Oxe, Kezia Catharina

AU - Badawi, Sara

AU - Nieto, Blanca

AU - Korsholm, Lea Milling

AU - Geisler, Sille Blangstrup

AU - Dulina, Ekaterina

AU - Rasmussen, Anna Vestergaard

AU - Dahl, Christina

AU - Lv, Wei

AU - Xu, Huixin

AU - Pan, Xiaoguang

AU - Arampatzis, Stefanos

AU - Stratou, Danai-Eleni

AU - Galanos, Panagiotis

AU - Lin, Lin

AU - Guldberg, Per

AU - Bartek, Jiri

AU - Luo, Yonglun

AU - Larsen, Dorthe H

PY - 2024/9/6

Y1 - 2024/9/6

N2 - 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.

AB - 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.

KW - Rad51 Recombinase/metabolism

KW - DNA, Ribosomal/genetics

KW - Humans

KW - RecQ Helicases/metabolism

KW - Genomic Instability

KW - Replication Protein A/metabolism

KW - Homologous Recombination

KW - Bloom Syndrome/genetics

KW - BRCA2 Protein/metabolism

KW - BRCA1 Protein/metabolism

KW - DNA Repair

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M3 - Journal article

C2 - 39242676

SN - 2041-1722

VL - 15

SP - 7797

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 7797

ER -

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

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