Transcription-Coupled Nucleotide Excision Repair Factors Promote R-Loop-Induced Genome Instability

doi:10.1016/J.MOLCEL.2014.10.020

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Transcription-Coupled Nucleotide Excision Repair Factors Promote R-Loop-Induced Genome Instability

Journal Article•DOI•

Transcription-Coupled Nucleotide Excision Repair Factors Promote R-Loop-Induced Genome Instability

Julie Sollier¹, Caroline Townsend Stork¹, María L. García-Rubio², Renee D. Paulsen¹, Andrés Aguilera², Karlene A. Cimprich¹ - Show less +2 more•Institutions (2)

Stanford University¹, Spanish National Research Council²

18 Dec 2014-Molecular Cell (Elsevier)-Vol. 56, Iss: 6, pp 777-785

TL;DR: Surprisingly, DSB formation requires the transcription-coupled nucleotide excision repair (TC-NER) factor Cockayne syndrome group B (CSB), but not the global genome repair protein XPC, which reveals an unexpected and potentially deleterious role for TC-NER factors in driving R-loop-induced DNA damage and genome instability.

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About: This article is published in Molecular Cell.The article was published on 2014-12-18 and is currently open access. It has received 434 citations till now. The article focuses on the topics: Nucleotide excision repair & DNA repair.

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Journal Article•DOI•

Roles of eukaryotic topoisomerases in transcription, replication and genomic stability

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Yves Pommier¹, Yilun Sun², Shar Yin N. Huang¹, John L. Nitiss²•Institutions (2)

National Institutes of Health¹, University of Illinois at Urbana–Champaign²

01 Nov 2016-Nature Reviews Molecular Cell Biology

TL;DR: The roles of topoisomerases in mediating chromatin dynamics, transcription, replication, DNA damage repair and genomic stability are reviewed, and how deregulation of top Loisomerases can cause neurodegenerative diseases, immune disorders and cancer are discussed.

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Abstract: Topoisomerases introduce transient DNA breaks to relax supercoiled DNA, remove catenanes and enable chromosome segregation. Human cells encode six topoisomerases (TOP1, TOP1mt, TOP2α, TOP2β, TOP3α and TOP3β), which act on a broad range of DNA and RNA substrates at the nuclear and mitochondrial genomes. Their catalytic intermediates, the topoisomerase cleavage complexes (TOPcc), are therapeutic targets of various anticancer drugs. TOPcc can also form on damaged DNA during replication and transcription, and engage specific repair pathways, such as those mediated by tyrosyl-DNA phosphodiesterase 1 (TDP1) and TDP2 and by endonucleases (MRE11, XPF-ERCC1 and MUS81). Here, we review the roles of topoisomerases in mediating chromatin dynamics, transcription, replication, DNA damage repair and genomic stability, and discuss how deregulation of topoisomerases can cause neurodegenerative diseases, immune disorders and cancer.

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650 citations

Journal Article•DOI•

R loops: new modulators of genome dynamics and function

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José M. Santos-Pereira¹, Andrés Aguilera¹•Institutions (1)

Spanish National Research Council¹

01 Oct 2015-Nature Reviews Genetics

TL;DR: The current knowledge of the mechanisms controlling R loops and their putative relationship with disease is reviewed and several DNA and RNA metabolism factors prevent R-loop formation in cells.

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Abstract: R loops are nucleic acid structures composed of an RNA-DNA hybrid and a displaced single-stranded DNA. Recently, evidence has emerged that R loops occur more often in the genome and have greater physiological relevance, including roles in transcription and chromatin structure, than was previously predicted. Importantly, however, R loops are also a major threat to genome stability. For this reason, several DNA and RNA metabolism factors prevent R-loop formation in cells. Dysfunction of these factors causes R-loop accumulation, which leads to replication stress, genome instability, chromatin alterations or gene silencing, phenomena that are frequently associated with cancer and a number of genetic diseases. We review the current knowledge of the mechanisms controlling R loops and their putative relationship with disease.

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595 citations

Journal Article•DOI•

R-Loops as Cellular Regulators and Genomic Threats.

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Madzia P Crossley¹, Michael J. Bocek¹, Karlene A. Cimprich¹•Institutions (1)

Stanford University¹

07 Feb 2019-Molecular Cell

TL;DR: This review highlights recent work suggesting that R-loops can be problematic to cells as blocks to efficient transcription and replication that trigger the DNA damage response and compares the available next-generation sequencing-based approaches to map R-loop genome wide.

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411 citations

Journal Article•DOI•

Transcription-Replication Conflict Orientation Modulates R-Loop Levels and Activates Distinct DNA Damage Responses.

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Stephan Hamperl¹, Michael J. Bocek¹, Joshua C. Saldivar¹, Tomek Swigut¹, Karlene A. Cimprich¹ - Show less +1 more•Institutions (1)

Stanford University¹

10 Aug 2017-Cell

TL;DR: These findings connect DNA replication to R-loop homeostasis and suggest a mechanistic basis for genome instability resulting from deregulated DNA replication, observed in cancer and other disease states.

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405 citations

Cites background from "Transcription-Coupled Nucleotide Ex..."

...Further studies will determine the structural intermediates formed upon HO and CD TRCs with an R-loop and the involvement of other factors implicated in processing RNADNA hybrids into DSBs such as the transcription-coupled nucleotide excision repair endonucleases (Sollier et al., 2014; Stork et al., 2016)....
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...…studies will determine the structural intermediates formed upon HO and CD TRCs with an R-loop and the involvement of other factors implicated in processing RNADNA hybrids into DSBs such as the transcription-coupled nucleotide excision repair endonucleases (Sollier et al., 2014; Stork et al., 2016)....
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...The loss of RNA processing and regulatory factors increases R-loop levels, causing R-loop-dependent DNA damage in both yeast and human cells (Huertas and Aguilera, 2003; Li and Manley, 2005; Paulsen et al., 2009; Santos-Pereira and Aguilera, 2015; Sollier et al., 2014)....
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Journal Article•DOI•

Regulation of Single-Strand Annealing and its Role in Genome Maintenance

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Ragini Bhargava¹, David O. Onyango¹, Jeremy M. Stark¹•Institutions (1)

City of Hope National Medical Center¹

01 Sep 2016-Trends in Genetics

TL;DR: The mechanism of SSA and its regulation is described, including the cellular conditions that may favor SSA versus other DSB repair events, and the potential contribution of Ssa to cancer-associated genome rearrangements, and to DSB-induced gene targeting.

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321 citations

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References

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Journal Article•DOI•

Instability and decay of the primary structure of DNA

[...]

Tomas Lindahl¹•Institutions (1)

University of Cambridge¹

22 Apr 1993-Nature

TL;DR: The spontaneous decay of DNA is likely to be a major factor in mutagenesis, carcinogenesis and ageing, and also sets limits for the recovery of DNA fragments from fossils.

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Abstract: Although DNA is the carrier of genetic information, it has limited chemical stability. Hydrolysis, oxidation and nonenzymatic methylation of DNA occur at significant rates in vivo, and are counteracted by specific DNA repair processes. The spontaneous decay of DNA is likely to be a major factor in mutagenesis, carcinogenesis and ageing, and also sets limits for the recovery of DNA fragments from fossils.

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5,209 citations

"Transcription-Coupled Nucleotide Ex..." refers background in this paper

...…been proposed that DNA damage may arise from the single-stranded DNA in the R-loop, because this DNA is more susceptible to DNA damaging agents (Lindahl, 1993) and could be targeted by enzymes like activationinduced cytidine deaminase (AID) that act at the immunoglobin ular Cell 56, 777–785,…...
[...]
...It has also been proposed that DNA damage may arise from the single-stranded DNA in the R-loop, because this DNA is more susceptible to DNA damaging agents (Lindahl, 1993) and could be targeted by enzymes like activationinduced cytidine deaminase (AID) that act at the immunoglobin...
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Journal Article•DOI•

Class Switch Recombination and Hypermutation Require Activation-Induced Cytidine Deaminase (AID), a Potential RNA Editing Enzyme

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Masamichi Muramatsu¹, Kazuo Kinoshita¹, Sidonia Fagarasan¹, Shuichi Yamada¹, Yoichi Shinkai¹, Tasuku Honjo¹ - Show less +2 more•Institutions (1)

Kyoto University¹

01 Sep 2000-Cell

TL;DR: Results suggest that AID may be involved in regulation or catalysis of the DNA modification step of both class switching and somatic hypermutation in CH12F3-2 B lymphoma.

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3,288 citations

"Transcription-Coupled Nucleotide Ex..." refers background in this paper

...It has also been proposed that DNA damage may arise from the single-stranded DNA in the R-loop, because this DNA is more susceptible to DNA damaging agents (Lindahl, 1993) and could be targeted by enzymes like activationinduced cytidine deaminase (AID) that act at the immunoglobin ular Cell 56, 777–785, December 18, 2014 ª2014 Elsevier Inc. 777 locus (Muramatsu et al., 2000)....
[...]
...Indeed, it has been shown that this processing depends upon AID (Muramatsu et al., 2000)....
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...However, AID is not expressed in most cells types, and no other specific factors have been shown to cause DNA damage when R-loops arise in cells....
[...]
...…in the R-loop, because this DNA is more susceptible to DNA damaging agents (Lindahl, 1993) and could be targeted by enzymes like activationinduced cytidine deaminase (AID) that act at the immunoglobin ular Cell 56, 777–785, December 18, 2014 ª2014 Elsevier Inc. 777 locus (Muramatsu et al., 2000)....
[...]

Journal Article•DOI•

Xeroderma Pigmentosum Group C Protein Complex Is the Initiator of Global Genome Nucleotide Excision Repair

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Kaoru Sugasawa¹, Jessica M. Y. Ng¹, Chikahide Masutani², Shigenori Iwai, Peter J. van der Spek¹, André P. M. Eker¹, Fumio Hanaoka², Dirk Bootsma¹, Jan H.J. Hoeijmakers¹ - Show less +5 more•Institutions (2)

Erasmus University Rotterdam¹, Osaka University²

01 Aug 1998-Molecular Cell

TL;DR: A novel DNA damage recognition-competition assay is used to identify XPC-HR23B as the earliest damage detector to initiate NER: it acts before the known damage-binding protein XPA, providing a plausible explanation for the extreme damage specificity exhibited by global genome repair.

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902 citations

"Transcription-Coupled Nucleotide Ex..." refers background in this paper

...XPC recognizes helix-distorting lesions during GG-NER and subsequently mobilizes NER proteins (Sugasawa et al., 1998)....
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Journal Article•DOI•

C9orf72 nucleotide repeat structures initiate molecular cascades of disease

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Aaron R. Haeusler¹, Christopher J. Donnelly¹, Goran Periz¹, Eric A J Simko¹, Patrick G. Shaw¹, Min-Sik Kim¹, Nicholas J. Maragakis¹, Juan C. Troncoso¹, Akhilesh Pandey¹, Rita Sattler¹, Jeffrey D. Rothstein¹, Jiou Wang¹ - Show less +8 more•Institutions (1)

Johns Hopkins University¹

13 Mar 2014-Nature

TL;DR: It is demonstrated that distinct C9orf72 HRE structural polymorphism at both DNA and RNA levels initiates molecular cascades leading to ALS/FTD pathologies, and provides the basis for a mechanistic model for repeat-associated neurodegenerative diseases.

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Abstract: A hexanucleotide repeat expansion (HRE), (GGGGCC)n, in C9orf72 is the most common genetic cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we identify a molecular mechanism by which structural polymorphism of the HRE leads to ALS/FTD pathology and defects. The HRE forms DNA and RNA G-quadruplexes with distinct structures and promotes RNA•DNA hybrids (R-loops). The structural polymorphism causes a repeat-length-dependent accumulation of transcripts aborted in the HRE region. These transcribed repeats bind to ribonucleoproteins in a conformation-dependent manner. Specifically, nucleolin, an essential nucleolar protein, preferentially binds the HRE G-quadruplex, and patient cells show evidence of nucleolar stress. Our results demonstrate that distinct C9orf72 HRE structural polymorphism at both DNA and RNA levels initiates molecular cascades leading to ALS/FTD pathologies, and provide the basis for a mechanistic model for repeat-associated neurodegenerative diseases.

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839 citations

"Transcription-Coupled Nucleotide Ex..." refers background in this paper

...…and Friedreich’s ataxia (Chen et al., 2004; Colak et al., 2014; Groh et al., 2014; Loomis et al., 2014), and they can cause genome instability at trinucleotide repeat sequences and common fragile sites, suggesting that they may contribute to cancer (Haeusler et al., 2014; Helmrich et al., 2011)....
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...Recently, the accumulation of R-loops has also been implicated in the silencing of critical genes that are associated with neurodegenerative diseases and which contain repeated DNA sequences (Colak et al., 2014; Groh et al., 2014; Haeusler et al., 2014; Loomis et al., 2014)....
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..., 2014), and they can cause genome instability at trinucleotide repeat sequences and common fragile sites, suggesting that they may contribute to cancer (Haeusler et al., 2014; Helmrich et al., 2011)....
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Journal Article•DOI•

R Loops: From Transcription Byproducts to Threats to Genome Stability

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Andrés Aguilera¹, Tatiana García-Muse¹•Institutions (1)

University of Seville¹

27 Apr 2012-Molecular Cell

TL;DR: The factors and cellular processes that control R loop formation and the mechanisms by which R loops may influence gene expression and the integrity of the genome are discussed.

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825 citations

"Transcription-Coupled Nucleotide Ex..." refers background in this paper

...These structures arise naturally in organisms from bacteria to humans, and they have a multitude of roles in the cell (Aguilera and Garcı́a-Muse, 2012; Skourti-Stathaki and Proudfoot, 2014; Hamperl and Cimprich, 2014)....
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...Although this is consistent with the known presence of RNA-DNA hybrids in these cellular compartments (El Hage et al., 2010; Aguilera and Garcı́a-Muse, 2012), we also found that the nucleolar S9....
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