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Trabectedin derails transcription-coupled nucleotide excision repair to induce DNA breaks in highly transcribed genes
The antitumor drug trabectedin is more toxic to DNA-repair-proficient cells. Here the authors show that this is caused by persistent DNA breaks induced from an abortive repair reaction and develop “TRABI-Seq” to map the breaks to transcribed regions of the genome. Trabectedin may thus be used as a diagnostic and therapeutic in precision oncology.
- Kook Son
- , Vakil Takhaveev
- & Orlando D. Schärer
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Nucleolar reorganization after cellular stress is orchestrated by SMN shuttling between nuclear compartments
DNA damage causes a major reorganization of the nucleolus. Here, the authors find that this structural restoration depends on the shuttling of the protein SMN from the Cajal bodies to the nucleolus, which requires coilin and PRMT1.
- Shaqraa Musawi
- , Lise-Marie Donnio
- & Giuseppina Giglia-Mari
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UV-induced G4 DNA structures recruit ZRF1 which prevents UV-induced senescence
Senescence can be activated in a DNA damage-dependent and -independent manner. Here the authors reveal in cell lines that recruitment of the factor ZRF1 at G4 DNA structures can prevents UV-induced senescence.
- Alessio De Magis
- , Michaela Limmer
- & Katrin Paeschke
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ASH1L-MRG15 methyltransferase deposits H3K4me3 and FACT for damage verification in nucleotide excision repair
Due to the naturally dense packing of the genome, DNA repair factors encounter a topologically very intricate cellular context. We describe how the human ASH1L protein navigates excision repair factors to accelerate their search for DNA lesions.
- Corina Maritz
- , Reihaneh Khaleghi
- & Hanspeter Naegeli
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Dynamic conformational switching underlies TFIIH function in transcription and DNA repair and impacts genetic diseases
The study unveils the structure, dynamics and regulatory mechanisms of the TFIIH protein assembly underpinning its divergent functions in gene expression and genome maintenance. Models link positions of TFIIH mutations to genetic disease phenotypes.
- Jina Yu
- , Chunli Yan
- & Ivaylo Ivanov
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Genomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients
Xeroderma pigmentosum (XP) is a rare genetic disorder that is associated with a higher risk of skin cancer. Here, the authors analyse the genomes of skin cancers from patients across five different XP groups, revealing genetic and molecular factors related to the mutational profile and UV-related mutagenesis in XP.
- Andrey A. Yurchenko
- , Fatemeh Rajabi
- & Sergey I. Nikolaev
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Active mRNA degradation by EXD2 nuclease elicits recovery of transcription after genotoxic stress
Here the authors show that the exonuclease EXD2 is involved in the recovery of class II gene transcription after UV irradiation. EXD2 travels from the mitochondria to the nucleus to interact with RNA Pol II and degrade new synthetized mRNA to allow transcription following DNA repair.
- Jérémy Sandoz
- , Max Cigrang
- & Frédéric Coin
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XPC–PARP complexes engage the chromatin remodeler ALC1 to catalyze global genome DNA damage repair
Cells employ global genome nucleotide excision repair to repair a broad spectrum of genomic DNA lesions. Here, the authors reveal how chromatin is primed for repair, providing insight into mechanisms of chromatin plasticity during DNA repair.
- Charlotte Blessing
- , Katja Apelt
- & Martijn S. Luijsterburg
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Pervasive Transcription-coupled DNA repair in E. coli
Transcription-Coupled DNA repair has been classically defined as the preferential repair of the template strand (TS) over the non-template strand (NTS). Here the authors challenge this classic model of TCR by using a genome-wide repair assay, CPD-seq, as well as RNA-seq, to show that TCR occurs across the entire E. coli genome – including NTS and intergenic regions.
- Britney Martinez
- , Binod K. Bharati
- & Evgeny Nudler
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Mechanism of Rad26-assisted rescue of stalled RNA polymerase II in transcription-coupled repair
Here the authors provide models of RNA polymerase II bound to the yeast CSB ortholog Rad26 in different nucleotide states; explain how Rad26 domain motions help the polymerase progress past DNA lesions; and interpret the effects of CSB-associated disease mutations.
- Chunli Yan
- , Thomas Dodd
- & Ivaylo Ivanov
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Cryo-EM structure of TFIIH/Rad4–Rad23–Rad33 in damaged DNA opening in nucleotide excision repair
The conserved eukaryotic nucleotide excision repair (NER) pathway protects the genome from a wide variety of environmentally induced DNA lesions. Here, the authors provide insights into how NER is initiated on lesions by determining the cryo-EM structure of the yeast TFIIH/Rad4–Rad23-Rad33 complex bound to a DNA containing a single carcinogen-DNA adduct.
- Trevor van Eeuwen
- , Yoonjung Shim
- & Kenji Murakami
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A CSB-PAF1C axis restores processive transcription elongation after DNA damage repair
The transcription-coupled repair pathway removes transcription-blocking DNA lesions, but how transcription is restored following DNA repair is not clear. Here the authors reveal that the PAF1 complex, while dispensable for the repair process, restores transcription after DNA damage.
- Diana van den Heuvel
- , Cornelia G. Spruijt
- & Martijn S. Luijsterburg
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Ubiquitin and TFIIH-stimulated DDB2 dissociation drives DNA damage handover in nucleotide excision repair
DNA damage sensors DDB2 and XPC are fundamental factors to initiate global genome nucleotide excision repair and protect DNA from mutagenesis. Here the authors reveal that ubiquitin and TFIIH-stimulated DDB2 dissociation promotes DNA damage handover to XPC in nucleotide excision repair.
- Cristina Ribeiro-Silva
- , Mariangela Sabatella
- & Hannes Lans
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Mutational signatures are jointly shaped by DNA damage and repair
Recent research has shown that mutational signatures reflective of the history of a cancer can be detected in a cancer genome. Here, using whole genome sequencing of DNA repair deficient and proficient nematodes exposed to genotoxins, the authors show that these mutational signatures reflect both the initial DNA damage that was inflicted and the repair processes that ensue.
- Nadezda V. Volkova
- , Bettina Meier
- & Moritz Gerstung
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The cooperative action of CSB, CSA, and UVSSA target TFIIH to DNA damage-stalled RNA polymerase II
The response to DNA damage-stalled RNA polymerase II leads to the assembly of the transcription-coupled repair (TCR) complex on actively transcribed strands. Here, the authors reveal the complex assembly mechanism of the TCR complex in human cells.
- Yana van der Weegen
- , Hadar Golan-Berman
- & Martijn S. Luijsterburg
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Single-molecule imaging reveals molecular coupling between transcription and DNA repair machinery in live cells
Mfd recognizes stalled transcriptional complexes at sites of lesions and recruits the nucleotide excision repair proteins (UvrAB) to the site. Here the authors use live cell imaging in E. coli to demonstrate that coordinated ATP hydrolysis by UvrA and loading of UvrB on DNA facilitate the dissociation of Mfd from the handoff complex.
- Han Ngoc Ho
- , Antoine M. van Oijen
- & Harshad Ghodke
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Single molecule analysis reveals monomeric XPA bends DNA and undergoes episodic linear diffusion during damage search
It is not fully understood how XPA interacts with a DNA lesion during nucleotide excision repair. Here, the authors use single molecule analysis to study XPA–DNA interactions, including the DNA bend angle, protein stoichiometry, and diffusive properties during damage search.
- Emily C. Beckwitt
- , Sunbok Jang
- & Bennett Van Houten
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DNA damage and transcription stress cause ATP-mediated redesign of metabolism and potentiation of anti-oxidant buffering
ERCC1 is involved in a number of DNA repair pathways including nucleotide excision repair. Here the authors showed that reduced transcription in Ercc1-deficient mouse livers and cells increases ATP levels, suppressing glycolysis and rerouting glucose into the pentose phosphate shunt that generates reductive stress.
- Chiara Milanese
- , Cíntia R. Bombardieri
- & Pier G. Mastroberardino
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Structural basis of TFIIH activation for nucleotide excision repair
The NER machinery contains the multisubunit transcription factor IIH (TFIIH) that opens the DNA repair bubble, scans for the lesion, and coordinates excision of the damaged site. Here the authors resolve the cryo-electron microscopy structure of the human core TFIIH-XPA-DNA complex and provide insights into its activation.
- Goran Kokic
- , Aleksandar Chernev
- & Patrick Cramer
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DNA damage sensitivity of SWI/SNF-deficient cells depends on TFIIH subunit p62/GTF2H1
SWI/SNF genes are commonly found to be mutated in different cancers. Here the authors report that the remodelers BRM and BRG1 are necessary for efficient nucleotide excision repair by promoting the expression of TFIIH subunit GTF2H1.
- Cristina Ribeiro-Silva
- , Özge Z. Aydin
- & Wim Vermeulen
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Genome-wide excision repair in Arabidopsis is coupled to transcription and reflects circadian gene expression patterns
Plants use nucleotide excision repair to maintain genome integrity in response to damage caused by stresses such as UV radiation. Here Oztas et al. use genome-wide profiling to show that excision repair in Arabidopsis is strongly coupled to transcription and reflects circadian patterns of gene expression.
- Onur Oztas
- , Christopher P. Selby
- & Ogun Adebali
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TRiC controls transcription resumption after UV damage by regulating Cockayne syndrome protein A
An integrated network of chaperones and protein degradation machineries called the proteostasis network (PN) is required to maintain protein homeostasis. Here the authors show that one of the components of the PN, the chaperonin TRiC, interacts with the core transcription-coupled nucleotide excision repair protein CSA to ensure its assembly into the CRLCSA complex.
- Alex Pines
- , Madelon Dijk
- & Haico van Attikum
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Global unleashing of transcription elongation waves in response to genotoxic stress restricts somatic mutation rate
Precise orchestration of gene expression regulation upon DNA damage is essential for genome integrity. Here the authors identify a novel widespread stress-triggered defence mechanism that promotes rapid transcription-driven genomic surveillance thus limiting mutagenesis and shaping cancer genomes.
- Matthieu D. Lavigne
- , Dimitris Konstantopoulos
- & Maria Fousteri
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ASH1L histone methyltransferase regulates the handoff between damage recognition factors in global-genome nucleotide excision repair
UV-induced mutagenic cyclobutane pyrimidine dimers on nucleosomal DNA are sensed by the damage recognition factors DDB2 and XPC via an unknown mechanism. Here, the authors show that the histone methyltransferase ASH1L regulates the DDB2 to XPC handoff by methylating Lys-4 of histone H3.
- Chiara Balbo Pogliano
- , Marco Gatti
- & Hanspeter Naegeli
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Phosphorylated HBO1 at UV irradiated sites is essential for nucleotide excision repair
Repair of cyclobutane pyrimidine dimers requires access to DNA by the nucleotide excision repair machinery. Here the authors show that HBO1 facilitates accumulation of SNF2H and ACF1 to make chromatin more accessible after ultraviolet damage.
- Hiroyuki Niida
- , Ryoichi Matsunuma
- & Masatoshi Kitagawa
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Single-molecule imaging of UvrA and UvrB recruitment to DNA lesions in living Escherichia coli
Nucleotide excision repair is able to identify and remove a wide range of DNA helix distorting lesions from the genome. Here the authors use single molecule imaging of UvrA and UvrB molecules and suggest a two-step ‘scan and recruit’ model for UvrA function.
- Mathew Stracy
- , Marcin Jaciuk
- & Pawel Zawadzki
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Telomeres are partly shielded from ultraviolet-induced damage and proficient for nucleotide excision repair of photoproducts
DNA damage caused by ultraviolet irradiation is removed from the genome by nucleotide excision repair; however, it is unclear if this occurs at chromosome ends. Here the authors provide evidence indicating that telomeres are partially shielded from damage and that repair is fully functional.
- Dhvani Parikh
- , Elise Fouquerel
- & Patricia L. Opresko
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SUMO and ubiquitin-dependent XPC exchange drives nucleotide excision repair
The SUMO-targeted ubiquitin ligase RNF111 promotes K63-linked ubiquitylation of SUMOylated XPC after DNA damage. Here the authors show that RNF111 is responsible for sequential XPC ubiquitylation, and RNF111-mediated ubiquitylation promotes the release of XPC from damaged DNA after NER initiation.
- Loes van Cuijk
- , Gijsbert J. van Belle
- & Jurgen A. Marteijn
Persistent TFIIH binding to non-excised DNA damage causes cell and developmental failure