Moving fast and breaking things: Incidence and repair of DNA damage within ribosomal DNA repeats

Abstract DNA damage poses a serious threat to human health and cells therefore continuously monitor and repair DNA lesions across the genome. Ribosomal DNA is a genomic domain that represents a particular challenge due to repetitive sequences, high transcriptional activity and its localization in the nucleolus, where the accessibility of DNA repair factors is limited. Recent discoveries have significantly extended our understanding of how cells respond to DNA double-strand breaks (DSBs) in the nucleolus, and new kinases and multiple down-stream targets have been identified. Restructuring of the nucleolus can occur as a consequence of DSBs and new data point to an active regulation of this process, challenging previous views. Furthermore, new insights into coordination of cell cycle phases and ribosomal DNA repair argue against existing concepts. In addition, the importance of nucleolar-DNA damage response (n-DDR) mechanisms for maintenance of genome stability and the potential of such factors as anti-cancer targets is becoming apparent. This review will provide a detailed discussion of recent findings and their implications for our understanding of the n-DDR. The n-DDR shares features with the DNA damage response (DDR) elsewhere in the genome but is also emerging as an independent response unique to ribosomal DNA and the nucleolus.

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SHPRH as a new player in ribosomal RNA transcription and its potential role in homeostasis of ribosomal DNA repeats

Transcription ◽

10.1080/21541264.2017.1381795 ◽

2017 ◽

Vol 9 (3) ◽

pp. 190-195 ◽

Cited By ~ 2

Author(s):

Deokjae Lee ◽

Jun Hong Park ◽

Shinseog Kim ◽

Seon-gyeong Lee ◽

Kyungjae Myung

Keyword(s):

Ribosomal Rna ◽

Ribosomal Dna ◽

Potential Role ◽

Dna Repeats ◽

Rna Transcription

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

PLoS Genetics ◽

10.1371/journal.pgen.1008511 ◽

2020 ◽

Vol 16 (6) ◽

pp. e1008511 ◽

Cited By ~ 2

Author(s):

Jérémie Fages ◽

Catherine Chailleux ◽

Jonathan Humbert ◽

Suk-Min Jang ◽

Jérémy Loehr ◽

...

Keyword(s):

Dna Damage ◽

Ribosomal Dna ◽

Dna Integrity

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UvrD Helicase Suppresses Recombination and DNA Damage-Induced Deletions

Journal of Bacteriology ◽

10.1128/jb.00275-06 ◽

2006 ◽

Vol 188 (15) ◽

pp. 5450-5459 ◽

Cited By ~ 21

Author(s):

Josephine Kang ◽

Martin J. Blaser

Keyword(s):

Dna Damage ◽

Mismatch Repair ◽

Excision Repair ◽

Critical Role ◽

Genotoxic Stress ◽

Recombinational Repair ◽

Dna Repeats ◽

H Pylori ◽

High Level

ABSTRACT UvrD, a highly conserved helicase involved in mismatch repair, nucleotide excision repair (NER), and recombinational repair, plays a critical role in maintaining genomic stability and facilitating DNA lesion repair in many prokaryotic species. In this report, we focus on the UvrD homolog in Helicobacter pylori, a genetically diverse organism that lacks many known DNA repair proteins, including those involved in mismatch repair and recombinational repair, and that is noted for high levels of inter- and intragenomic recombination and mutation. H. pylori contains numerous DNA repeats in its compact genome and inhabits an environment rich in DNA-damaging agents that can lead to increased rearrangements between such repeats. We find that H. pylori UvrD functions to repair DNA damage and limit homologous recombination and DNA damage-induced genomic rearrangements between DNA repeats. Our results suggest that UvrD and other NER pathway proteins play a prominent role in maintaining genome integrity, especially after DNA damage; thus, NER may be especially critical in organisms such as H. pylori that face high-level genotoxic stress in vivo.

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The retrotransposon R2 maintains Drosophila ribosomal DNA repeats

10.1101/2021.07.12.451825 ◽

2021 ◽

Author(s):

Jonathan O Nelson ◽

Alyssa Slicko ◽

Yukiko M Yamashita

Keyword(s):

Ribosomal Dna ◽

Copy Number ◽

Double Strand Breaks ◽

Copy Number Loss ◽

Dna Repeats ◽

Dna Double Strand Breaks ◽

Strand Breaks ◽

Male Germline ◽

Rdna Loci ◽

Rdna Copy

Ribosomal RNAs (rRNAs) account for 80-90% of all transcripts in eukaryotic cells. To meet this demand, the ribosomal DNA (rDNA) gene that codes for rRNA is tandemly repeated hundreds of times, comprising rDNA loci on eukaryotic chromosomes. This repetitiveness imposes a challenge to maintaining sufficient copy number due to spontaneous intra-chromatid recombination between repetitive units causing copy number loss. The progressive shrinking of rDNA loci from generation to generation could lead to extinction of the lineage, yet the mechanism(s) to counteract spontaneous copy number loss remained unclear. Here, we show that the rDNA-specific retrotransposon R2 is essential for rDNA copy number (CN) maintenance in the Drosophila male germline, despite the perceived disruptive nature of transposable elements. Depletion of R2 led to defective rDNA CN maintenance in multiple contexts, causing a decline in fecundity over generations and eventual extinction of the lineage. Our data suggests that DNA double strand breaks generated by R2 is the initiating event of rDNA CN expansion, stimulating the repair processes proposed to underlie rDNA CN expansion. This study reveals that retrotransposons can provide a benefit to their hosts, contrary to their reputation as genomic parasitic, which may contribute to their widespread success throughout taxa.

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The inhibition of checkpoint activation by telomeres does not involve exclusion of dimethylation of histone H4 lysine 20 (H4K20me2)

F1000Research ◽

10.12688/f1000research.15166.1 ◽

2018 ◽

Vol 7 ◽

pp. 1027

Author(s):

Julien Audry ◽

Jinyu Wang ◽

Jessica R. Eisenstatt ◽

Kathleen L. Berkner ◽

Kurt W. Runge

Keyword(s):

Dna Damage ◽

Protein Complexes ◽

Dna Damage Checkpoint ◽

Short Report ◽

Dna Repeats ◽

Histone H4 ◽

Wild Type ◽

Telomeric Dna ◽

Checkpoint Signaling ◽

Eukaryotic Chromosome

DNA double-strand (DSBs) breaks activate the DNA damage checkpoint machinery to pause or halt the cell cycle. Telomeres, the specific DNA-protein complexes at linear eukaryotic chromosome ends, are capped DSBs that do not activate DNA damage checkpoints. This “checkpoint privileged” status of telomeres was previously investigated in the yeast Schizosaccharomyces pombe lacking the major double-stranded telomere DNA binding protein Taz1. Telomeric DNA repeats in cells lacking Taz1 are 10 times longer than normal and contain single-stranded DNA regions. DNA damage checkpoint proteins associate with these damaged telomeres, but the DNA damage checkpoint is not activated. This severing of the DNA damage checkpoint signaling pathway was reported to stem from exclusion of histone H4 lysine 20 dimethylation (H4K20me2) from telomeric nucleosomes in both wild type cells and cells lacking Taz1. However, experiments to identify the mechanism of this exclusion failed, prompting our re-evaluation of H4K20me2 levels at telomeric chromatin. In this short report, we used an extensive series of controls to identify an antibody specific for the H4K20me2 modification and show that the level of this modification is the same at telomeres and internal loci in both wild type cells and those lacking Taz1. Consequently, telomeres must block activation of the DNA Damage Response by another mechanism that remains to be determined.

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RNase H enables efficient repair of R-loop induced DNA damage

10.1101/068742 ◽

2016 ◽

Author(s):

Jeremy D. Amon ◽

Douglas Koshland

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Ribosomal Dna ◽

Genome Instability ◽

Rnase H ◽

Rna Polymerase I ◽

Chromosomal Dna ◽

Polymerase I ◽

Break Induced Replication ◽

Kinetics Of

AbstractR-loops, three-stranded structures that form when transcripts hybridize to chromosomal DNA, are potent agents of genome instability. This instability has been explained by the ability of R-loops to induce DNA damage. Here, we show that persistent R-loops also compromise DNA repair. Depleting endogenous RNase H activity impairs R-loop removal in budding yeast, causing DNA damage that occurs preferentially in the repetitive ribosomal DNA locus (rDNA). We analyzed the repair kinetics of this damage and identified mutants that modulate repair. Our results indicate that persistent R-loops in the rDNA induce damage that is slowly repaired by break-induced replication (BIR). Furthermore, R-loop induced BIR at the rDNA leads to lethal repair intermediates when RNA polymerase I elongation is compromised. We present a model to explain how removal of R-loops by RNase H is critical in ensuring the efficient repair of R-loop induced DNA damage by pathways other than BIR.

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CTCF regulates the local epigenetic state of ribosomal DNA repeats

Epigenetics & Chromatin ◽

10.1186/1756-8935-3-19 ◽

2010 ◽

Vol 3 (1) ◽

pp. 19 ◽

Cited By ~ 56

Author(s):

Suzanne van de Nobelen ◽

Manuel Rosa-Garrido ◽

Joerg Leers ◽

Helen Heath ◽

Widia Soochit ◽

...

Keyword(s):

Ribosomal Dna ◽

Dna Repeats ◽

Epigenetic State

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Evaluation of genotoxicity of acetamiprid using PCR technique on mosquito genome

Journal of Applied and Natural Science ◽

10.31018/jans.v3i2.179 ◽

2011 ◽

Vol 3 (2) ◽

pp. 200-205

Author(s):

Mamta Bansal ◽

Gurjeet Kaur ◽

Asha Chaudhry

Keyword(s):

Polymerase Chain Reaction ◽

Dna Damage ◽

Ribosomal Dna ◽

Culex Quinquefasciatus ◽

Internal Transcribed Spacer ◽

Gene Mutations ◽

Polymerase Chain Reaction Technique ◽

Chain Reaction ◽

Polymerase Chain ◽

Transitions And Transversions

The present studies deal with the evaluation of the genotoxic potential of acetamiprid at LD40 on a mosquito Culex quinquefasciatus by adopting polymerase chain reaction technique (PCR). This technique was used for detecting DNA damage by amplifying ribosomal DNA internal transcribed spacer 2 (ITS 2) regions. The amplified products were sequenced and the results of treated and non-treated controls were compared using Clustal W software programme. The results were studied in the form of deletions, additions, transitions and transversions of the bases. The DNA band amplified from control stocks consisted of 444 bases while those from LD40 treated individuals were comprised of 448 bases. The total number of mutations caused in the treated stock was 230 out of which 84 were transitions, 117 transversions, 13 deletions and 16 additions. Thus, it was evident that acetamiprid has a potential to promote gene mutations in the individuals exposed to its semilethal doses.

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