Ribosomal DNA copy loss and repeat instability in ATRX-mutated cancers

Udugama, Maheshi; Sanij, Elaine; Voon, Hsiao P.J.; Son, Jinbae; Hii, Linda; Henson, Jeremy D.; Chan, F. Lyn; Chang, Fiona T. M.; Liu, Yumei; Pearson, Richard B.; Kalitsis, Paul; Mann, Jeffrey R.; Collas, Philippe; Hannan, Ross D.; Wong, Lee H.

doi:10.1073/pnas.1720391115

Cited by 80 publications

(74 citation statements)

References 31 publications

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“…In summary, we identified here a new factor participating in the maintenance of rDNA integrity. The importance of such mechanism is highlighted by the increasing number of studies showing the involvement of rDNA repeats integrity in a number of disease such as cancer, neurological-and aging-associated diseases most of them in relationship with gene products associated with the genome maintenance [4,8].…”

Section: Discussionmentioning

confidence: 99%

“…Maintaining the number of rDNA repeats as well as the level of transcription is crucial for cellular homeostasis [3]. Instability of the rDNA repeats was reported in cancer [4] and Bloom and ataxia-telangectasia cell lines [5,6]. Therefore, DSBs generated in rDNA need to be efficiently and accurately repaired in particular to prevent recombination events that could result in loss of repeats in such repetitive regions.…”

Section: Introductionmentioning

confidence: 99%

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JMJD6 participates in the maintenance of ribosomal DNA integrity in response to DNA damage

Fages

Chailleux

Humbert

et al. 2019

Preprint

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Ribosomal DNA (rDNA) is the most transcribed genomic region and contains hundreds of tandem repeats. Maintaining these rDNA repeats as well as the level of rDNA transcription is essential for cellular homeostasis. DNA damages generated in rDNA need to be efficiently and accurately repaired as rDNA repeats instability has been reported in cancer, aging and neurological diseases. Here, we describe that the histone demethylase JMJD6 is rapidly recruited at nucleolar DNA damage and is crucial for the relocalisation of rDNA in nucleolar caps. Yet, JMJD6 is dispensable for rDNA transcription inhibition. Mass spectrometry study revealed that JMJD6 interacts with the nucleolar protein Treacle and modulates its interaction with NBS1. Moreover, 2 cells deficient for JMJD6 show increased sensitivity to nucleolar DNA damage as well as loss and rearrangements of rDNA repeats upon irradiation. Altogether our data reveals that rDNA transcription inhibition is uncoupled from rDNA relocalisation into nucleolar caps and that JMJD6 is required for rDNA stability upon the rDNA damage response through its role in nucleolar caps formation. Author summary:Ribosomal DNA is the most transcribed genomic region composed of repeated sequences. Transcribed rDNA is essential for cellular homeostasis and cell proliferation. Numerous pathologies such as cancer and neurological disorders are described to present defective rDNA repeats maintenance. The mechanisms involved in the control of rDNA integrity involve major DNA repair pathways such as NonHomologous End-Joining and Homologous Recombination. However, how they are controlled and orchestrated is poorly understood. Here, we identified JMJD6 as a new member of the maintenance of rDNA integrity. We observed that JMJD6 controls the recruitment of NBS1 in the nucleolus in order to lead to the proper response to DNA damage at rDNA repeats. short title: maintenance of ribosomal DNA in response to DNA damage 3 Author contributions: YC and DT wrote the manuscript with input from their coauthors. JF, CC, JH, S-KM, JL, J-PL and YC performed the experiments. JC supervised JF and JH during purification and mass spectrometry analysis. YC and DT conceived the project, designed research and coordinated the studies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

JMJD6 participates in the maintenance of ribosomal DNA integrity in response to DNA damage

Fages

Chailleux

Humbert

et al. 2019

Preprint

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“…Indeed, both of these conditions were identified in different human cancer types (Udugama et al 2018; Wang and Lemos 2017; Xu et al 2017). Increased rRNA transcription is a ubiquitous and well-known hallmark of cancer cells and the resulting increased nucleolar sizes were used as diagnostic marker by pathologists.…”

Section: Human Rdna Nucleolar Morphology and Rrna Transcriptionmentioning

confidence: 99%

Nucleolus and chromatin

Schöfer

Weipoltshammer

2018

Histochem Cell Biol

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The nucleolus as site of ribosome biogenesis holds a pivotal role in cell metabolism. It is composed of ribosomal DNA (rDNA), which is present as tandem arrays located in nucleolus organizer regions (NORs). In interphase cells, rDNA can be found inside and adjacent to nucleoli and the location is indicative for transcriptional activity of ribosomal genes—inactive rDNA (outside) versus active one (inside). Moreover, the nucleolus itself acts as a spatial organizer of non-nucleolar chromatin. Microscopy-based approaches offer the possibility to explore the spatially distinct localization of the different DNA populations in relation to the nucleolar structure. Recent technical developments in microscopy and preparatory methods may further our understanding of the functional architecture of nucleoli. This review will attempt to summarize the current understanding of mammalian nucleolar chromatin organization as seen from a microscopist’s perspective.

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“…In this study, we paid attention to human ribosomal DNA (rDNA) repeat unit, which repeats hundreds of times in diploid human genome. Human rDNA clusters on the short arms of the five acrocentric chromosomes (chromosomes 13,14,15,21,22), and contains a 13-kb transcribed region and a 30-kb intergenic spacer (IGS). Transcribed region encodes 18S, 5.8S and 28S ribosomal RNA.…”

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confidence: 99%

“…Copy number variation of rDNA balances rDNA dosage [17]and is associated with the expression of several functional coherent gene sets [18]. rDNA copy number amplification or deletion is related to tumor genetic context, nucleolus activity, proliferation and protein activity in different cancer types [19][20][21][22]. The expression of rDNA also shows aberrant patterns in prostate cancer, cervical cancer, breast cancer and myelodysplastic syndromes [23][24][25][26].…”

mentioning

confidence: 99%

Ribosomal DNA methylation as stable biomarkers for detection of cancer in plasma

Zhang

Fang

Zhang

et al. 2019

Preprint

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BackgroundRecently, liquid biopsy for cancer detection has pursued great progress. However, there are still a lack of high quality markers. It is a challenge to detect cancer stably and accurately in plasma cell free DNA (cfDNA), when the ratio of cancer signal is low. Repetitive genes or elements may improve the robustness of signals. In this study, we focused on ribosomal DNA which repeats hundreds of times in human diploid genome and investigated performances for cancer detection in plasma. ResultsWe collected bisulfite sequencing samples including normal tissues and 4 cancer types and found that intergenic spacer (IGS) of rDNA has high methylation levels and low variation in normal tissues and plasma. Strikingly, IGS of rDNA shows significant hypo-methylation in tumors compared with normal tissues. Further, we collected plasma bisulfite sequencing data from 224 healthy subjects and cancer patients. Means of AUC in testing set were 0.96 (liver cancer), 0.94 (lung cancer and), 0.92 (colon cancer) with classifiers using only 10 CpG sites. Due to the feature of high copy number, when liver cancer plasma WGBS was down-sampled to 10 million raw reads (0.25× whole genome coverage), the prediction performance decreased only a bit (mean AUC=0.93). Finally, methylation of rDNA could also be used for monitor cancer progression and treatment. ConclusionTaken together, we provided the high-resolution map of rDNA methylation in tumors and supported that methylation of rDNA was a competitive and robust marker for detecting cancer and monitoring cancer progression in plasma.

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Ribosomal DNA copy loss and repeat instability in ATRX-mutated cancers

Cited by 80 publications

References 31 publications

JMJD6 participates in the maintenance of ribosomal DNA integrity in response to DNA damage

JMJD6 participates in the maintenance of ribosomal DNA integrity in response to DNA damage

Nucleolus and chromatin

Ribosomal DNA methylation as stable biomarkers for detection of cancer in plasma

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