Transcription-coupled repair: an update

Spivak, Graciela

doi:10.1007/s00204-016-1820-x

Cited by 52 publications

(44 citation statements)

References 91 publications

(111 reference statements)

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“…2). Backtracking of the EC exposes the lesion to UvrABC, thereby promoting repair [32][56][10]. This action of UvrD may be succeeded by its function in dissociating the oligonucleotide resulting from the double incision of the DNA.…”

Section: Tcr In E Colimentioning

confidence: 99%

“…In addition to marking DNA damage, RNAP provides another advantage to TCR by transiently opening the nucleosome structure during transcription [10]. Although the sequence of events in human TCR is similar to that in bacteria, the process is more complicated with respect to the number of proteins involved and their interplay [12][82].…”

Section: Tcr In Human Cellsmentioning

confidence: 99%

“…The lesion-bearing oligonucleotide is then expelled and new DNA is synthesized using the undamaged strand as a template. Finally, the new DNA is ligated to the adjacent strand [10][11][12]. Blockage of the RNAP at the damaged site is the general trigger for TCR [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

“…Several of these mutations have also been linked to cancer and aging [20][21][22]. The severe developmental problems that characterize Cockayne syndrome do not occur in UV-sensitive syndrome even though the causal mutations can be in either CSA or CSB [10]. However, non-productive engagement of TCR at or near naturally occurring non-canonical DNA structures can be mutagenic [12][23].…”

Section: Introductionmentioning

confidence: 99%

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Mechanistic insights into transcription coupled DNA repair

Pani

Nudler

2017

DNA Repair

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Transcription-coupled DNA repair (TCR) acts on lesions in the transcribed strand of active genes. Helix distorting adducts and other forms of DNA damage often interfere with the progression of the transcription apparatus. Prolonged stalling of RNA polymerase can promote genome instability and also induce cell cycle arrest and apoptosis. These generally unfavorable events are counteracted by RNA polymerase-mediated recruitment of specific proteins to the sites of DNA damage to perform TCR and eventually restore transcription. In this perspective we discuss the decision-making process to employ TCR and we elucidate the intricate biochemical pathways leading to TCR in E. coli and human cells.

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Section: Tcr In E Colimentioning

confidence: 99%

Section: Tcr In Human Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mechanistic insights into transcription coupled DNA repair

Pani

Nudler

2017

DNA Repair

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“…2 The two subpathways of NER, global genomic NER (GG-NER) and transcription-coupled NER (TC-NER), employ a common set of proteins including TFIIH, XPG, XPA, RPA, and ERCC1-XPF, and are essentially the same except for differences in their lesion-recognition mechanisms. 2,12−15 In TC-NER, the RNA polymerase acts as the lesion sensor; in our current focus of GG-NER, the XPC-RAD23B complex detects lesion-containing DNA, aided in cells by centrin 2 and UV-DDB1/2 for cyclobutane pyrimidine dimers (CPDs). 16−20 UV-DDB1/2 is believed to hand off CPD lesions to XPC, 2,21 and studies with CPD lesions in cells suggest that UV-DDB1/2 facilitates NER in chromatin.…”

Section: Introductionmentioning

confidence: 99%

Nucleotide Excision Repair Lesion-Recognition Protein Rad4 Captures a Pre-Flipped Partner Base in a Benzo[a]pyrene-Derived DNA Lesion: How Structure Impacts the Binding Pathway

Mu¹,

Geacintov²,

Min

et al. 2017

Chem. Res. Toxicol.

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The xeroderma pigmentosum C protein complex (XPC) recognizes a variety of environmentally induced DNA lesions and is the key in initiating their repair by the nucleotide excision repair (NER) pathway. When bound to a lesion, XPC flips two nucleotide pairs that include the lesion out of the DNA duplex, yielding a productively bound complex that can lead to successful lesion excision. Interestingly, the efficiencies of NER vary greatly among different lesions, influencing their toxicity and mutagenicity in cells. Though differences in XPC binding may influence NER efficiency, it is not understood whether XPC utilizes different mechanisms to achieve productive binding with different lesions. Here, we investigated the well-repaired 10R-(+)-cis-anti-benzo[a]pyrene-N2-dG (cis-B[a]P-dG) DNA adduct in a duplex containing normal partner C opposite the lesion. This adduct is derived from the environmental pro-carcinogen benzo[a]pyrene and is likely to be encountered by NER in the cell. We have extensively investigated its binding to the yeast XPC orthologue, Rad4, using umbrella sampling with restrained molecular dynamics simulations and free energy calculations. The NMR solution structure of this lesion in duplex DNA has shown that the dC complementary to the adducted dG is flipped out of the DNA duplex in the absence of XPC. However, it is not known whether the “pre-flipped” base would play a role in its recognition by XPC. Our results show that Rad4 first captures the displaced dC, which is followed by a tightly coupled lesion-extruding pathway for productive binding. This binding path differs significantly from the one deduced for the small cis-syn cyclobutane pyrimidine dimer lesion opposite mismatched thymines [MuH.MuH.26270861Biochemistry20155452637]. The possibility of multiple paths that lead to productive binding to XPC is consistent with the versatile lesion recognition by XPC that is required for successful NER.

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Mechanistic understanding of cellular responses to genomic stress

Hanawalt

Sweasy

2019

Environ and Mol Mutagen

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Within the past half century we have learned of multiple pathways for repairing damaged DNA, based upon the intrinsic redundancy of information in its complementary double strands. Mechanistic details of these pathways have provided insights into environmental and endogenous threats to genomic stability. Studies on bacterial responses to ultraviolet light led to the discovery of excision repair, as well as the inducible SOS response to DNA damage. Similar responses in eukaryotes promote upregulation of error‐prone translesion DNA polymerases. Recent advances in this burgeoning field include duplex DNA sequencing to provide strikingly accurate profiling of mutational signatures, analyses of gene expression patterns in single cells, CRISPR/Cas9 to generate changes at precise genomic positions, novel roles for RNA in gene expression and DNA repair, phase‐separated aqueous environments for specialized cellular transactions, and DNA lesions as epigenetic signals for gene expression. The Environmental Mutagenesis and Genomics Society (EMGS), through the broad range of expertise in its membership, stands at the crossroad of basic understanding of mechanisms for genomic maintenance and the field of genetic toxicology, with the need for regulation of exposures to toxic substances. Our future challenges include devising strategies and technologies to identify individuals who are susceptible to specific genomic stresses, along with basic research on the underlying mechanisms of cellular stress responses that promote disease‐causing mutations. As the science moves forward it should also be a responsibility for the EMGS to expand its outreach programs for the enlightenment and benefit of all humans and the biosphere. Environ. Mol. Mutagen. 61:25–33, 2020. © 2019 Wiley Periodicals, Inc.

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Transcription-coupled repair: an update

Cited by 52 publications

References 91 publications

Mechanistic insights into transcription coupled DNA repair

Mechanistic insights into transcription coupled DNA repair

Nucleotide Excision Repair Lesion-Recognition Protein Rad4 Captures a Pre-Flipped Partner Base in a Benzo[a]pyrene-Derived DNA Lesion: How Structure Impacts the Binding Pathway

Mechanistic understanding of cellular responses to genomic stress

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