Nucleotide Excision Repair and Transcription‐Associated Genome Instability

Apostolou, Zivkos; Chatzinikolaou, Georgia; Stratigi, Kalliopi; Garinis, George A.

doi:10.1002/bies.201800201

Cited by 31 publications

(27 citation statements)

References 135 publications

(198 reference statements)

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“…Most research targets are directly related to chromosomal machineries, including DNA replication/repair, chromatin condensation, condensed chromosome segregation, and regulators of cell cycle checking points. Traditionally, for example, gene mutations responsible for chromosome instability syndromes and drugs that can directly interfere with chromosomal machineries were frequently under investigation [ 38 , 39 , 40 , 41 ].…”

Section: Stress As a Hidden Link: All Roads Lead To Cinmentioning

confidence: 99%

Origins and Consequences of Chromosomal Instability: From Cellular Adaptation to Genome Chaos-Mediated System Survival

Sharpe

Heng

2020

Genes

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When discussing chromosomal instability, most of the literature focuses on the characterization of individual molecular mechanisms. These studies search for genomic and environmental causes and consequences of chromosomal instability in cancer, aiming to identify key triggering factors useful to control chromosomal instability and apply this knowledge in the clinic. Since cancer is a phenomenon of new system emergence from normal tissue driven by somatic evolution, such studies should be done in the context of new genome system emergence during evolution. In this perspective, both the origin and key outcome of chromosomal instability are examined using the genome theory of cancer evolution. Specifically, chromosomal instability was linked to a spectrum of genomic and non-genomic variants, from epigenetic alterations to drastic genome chaos. These highly diverse factors were then unified by the evolutionary mechanism of cancer. Following identification of the hidden link between cellular adaptation (positive and essential) and its trade-off (unavoidable and negative) of chromosomal instability, why chromosomal instability is the main player in the macro-cellular evolution of cancer is briefly discussed. Finally, new research directions are suggested, including searching for a common mechanism of evolutionary phase transition, establishing chromosomal instability as an evolutionary biomarker, validating the new two-phase evolutionary model of cancer, and applying such a model to improve clinical outcomes and to understand the genome-defined mechanism of organismal evolution.

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Section: Stress As a Hidden Link: All Roads Lead To Cinmentioning

confidence: 99%

Origins and Consequences of Chromosomal Instability: From Cellular Adaptation to Genome Chaos-Mediated System Survival

Sharpe

Heng

2020

Genes

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“…Pulldown experiments in nuclear extracts of bXPF and control BirA MEFs confirmed that the endogenous bXPF interacts with the TATA-associated factors (TAFs) TAF4, TAF6, and TAF10 of the TFIID complex (Kamileri et al, 2012c) as well as with CTCF and the cohesin subunits SMC1A and SMC3 ( Figure 5A and Figure 5B ) (Chatzinikolaou et al, 2017) highlighting the possible role of ERCC1-XPF complex in transcription initiation and chromatin looping (Apostolou et al, 2019; Kamileri et al, 2012a). Moreover, these findings along with the preferential recruitment of bXPF on promoters upon transcription stimulation ( Figure 2B-C ) and the identification of several topoisomerases in the 607 bXPF-bound core proteome ( Figure 4G ) fit well with the known involvement of ERCC1-XPF in DNA DSB repair (Ahmad et al, 2008; Li et al, 2019).…”

Section: Resultsmentioning

confidence: 90%

“…We previously showed that ERCC1-XPF engages together with RNAPII and the basal transcription machinery at the promoters of growth genes during postnatal hepatic development (Apostolou et al, 2019; Kamileri et al, 2012a; Kamileri et al, 2012b). However, the structure-specific requirement of ERCC1-XPF for incision made it difficult to justify the functional role of the endonuclease complex on promoters.…”

Section: Discussionmentioning

confidence: 99%

“…The generation and characterization of Biotin-tagged XPF (bXPF) and NER-deficient mice has been previously described (Apostolou et al, 2019; Chatzinikolaou et al, 2017; Kamileri et al, 2012a; Kamileri et al, 2012b). Animals were kept on a regular diet and housed at the IMBB animal house, which operates in compliance with the “Animal Welfare Act” of the Greek government, using the “Guide for the Care and Use of Laboratory Animals” as its standard.…”

Section: Methodsmentioning

confidence: 99%

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ERCC1-XPF Interacts with Topoisomerase IIβ to Facilitate the Repair of Activity-induced DNA Breaks

Chatzinikolaou

Stratigi

Agathangelou

et al. 2020

Preprint

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Type II DNA Topoisomerases (TOP II) generate transient double-strand DNA breaks (DSBs) to resolve topological constraints during transcription. Using genome-wide mapping of DSBs and functional genomics approaches, we show that, in the absence of exogenous genotoxic stress, transcription leads to DSB accumulation and to the recruitment of the structure-specific ERCC1-XPF endonuclease on active gene promoters. Instead, we find that the complex is released from regulatory or gene body elements in UV-irradiated cells. Abrogation of ERCC1 or re-ligation blockage of TOP II-mediated DSBs aggravates the accumulation of transcription-associated γ H2Ax and 53BP1 foci, which dissolve when TOP II-mediated DNA cleavage is inhibited. An in vivo biotinylation tagging strategy coupled to a high-throughput proteomics approach reveals that ERCC1-XPF interacts with TOP IIβ and the CTCF/cohesin complex, which co-localize with the heterodimer on DSBs.Together; our findings provide a rational explanation for the remarkable clinical heterogeneity seen in human disorders with ERCC1-XPF defects. 8 indicate that, in the absence of exogenous genotoxic stimuli, transcription initiation, but not elongation, triggers an ATM-dependent DDR that is further pronounced in cells defective in the ERCC1-XPF endonuclease.

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“…Inborn defects in RNA processing or DNA repair associate with progeria [53][54][55] , the metabolic syndrome [56][57][58] , neurodegeneration [59][60][61][62] and cancer [63][64][65][66][67] , arguing for functional links between genome maintenance and the splicing machinery in development or disease. Using an in vivo biotinylation tagging approach in mice, we nd that XAB2 interacts with components of the core spliceosome as well as with DDB1 involved in UV-induced DNA damage recognition and XPA that plays a prominent role in the assembly of the NER incision complex at sites of DNA damage 62,68 . As DDB1 is successfully recruited to UV-induced CPDs in siXab2 cells, the implication of XAB2:DDB1 interaction remains elusive.…”

Section: Discussionmentioning

confidence: 99%

The Splicing Factor XAB2 interacts with ERCC1-XPF and XPG for RNA-loop processing during mammalian development

Goulielmaki

Tsekrekou

Batsiotos

et al. 2020

Preprint

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RNA splicing, transcription and the DNA damage response are intriguingly linked in mammals but the underlying mechanisms remain poorly understood. Using an in vivo biotinylation tagging approach in mice, we show that the splicing factor XAB2 interacts with the core spliceosome and that it binds to spliceosomal U4 and U6 snRNAs and pre-mRNAs in developing livers. XAB2 depletion leads to aberrant intron retention, R-loop formation and DNA damage in cells. Studies in illudin S-treated cells and Csbm/m developing livers reveal that transcription-blocking DNA lesions trigger the release of XAB2 from all RNA targets tested. Immunoprecipitation studies reveal that XAB2 interacts with ERCC1-XPF and XPG endonucleases outside nucleotide excision repair and that the trimeric protein complex binds RNA:DNA hybrids under conditions that favor the formation of R-loops. Thus, XAB2 functionally links the spliceosomal response to DNA damage with R-loop processing with important ramifications for mammalian development and transcription-coupled DNA repair disorders.

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Nucleotide Excision Repair and Transcription‐Associated Genome Instability

Cited by 31 publications

References 135 publications

Origins and Consequences of Chromosomal Instability: From Cellular Adaptation to Genome Chaos-Mediated System Survival

Origins and Consequences of Chromosomal Instability: From Cellular Adaptation to Genome Chaos-Mediated System Survival

ERCC1-XPF Interacts with Topoisomerase IIβ to Facilitate the Repair of Activity-induced DNA Breaks

The Splicing Factor XAB2 interacts with ERCC1-XPF and XPG for RNA-loop processing during mammalian development

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