Molecular basis of transcriptional fidelity and DNA lesion-induced transcriptional mutagenesis

Xu, Liang; Da, Lin-Tai; Plouffe, Steven W.; Chong, Jenny; Kool, Eric T.; Wang, Dong

doi:10.1016/j.dnarep.2014.03.024

Cited by 28 publications

(25 citation statements)

References 169 publications

(182 reference statements)

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“…We further note that weak or transient POL IV association to chromatin may not be necessarily incompatible with production of biologically relevant sRNAs, which, like uviRNAs and diRNAs, are unrelated to RdDM, the main function ascribed so far to POL IV as part of the machinery producing conventional heterochromatic siRNAs. Upon UV irradiation, RNA POL II is usually removed from the lesions of transcribed genomic regions via ubiquitin-dependent proteolytic degradation allowing TCR (48), although lesion bypass may be also used alternatively (49). Photolesions might similarly interfere with RNA POL IV stability, possibly explaining its weak or transient interaction with chromatin at uviRNA-generating loci.…”

Section: A Model For Dna Repair Mediated By Uvirnas and Their Possiblementioning

confidence: 99%

Small RNA-mediated repair of UV-induced DNA lesions by the DNA DAMAGE-BINDING PROTEIN 2 and ARGONAUTE 1

Schalk

Cognat

Graindorge

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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As photosynthetic organisms, plants need to prevent irreversible UV-induced DNA lesions. Through an unbiased, genome-wide approach, we have uncovered a previously unrecognized interplay between Global Genome Repair and small interfering RNAs (siRNAs) in the recognition of DNA photoproducts, prevalently in intergenic regions. Genetic and biochemical approaches indicate that, upon UV irradiation, the DNA DAMAGE-BINDING PROTEIN 2 (DDB2) and ARGONAUTE 1 (AGO1) of Arabidopsis thaliana form a chromatin-bound complex together with 21-nt siRNAs, which likely facilitates recognition of DNA damages in an RNA/DNA complementary strand-specific manner. The biogenesis of photoproduct-associated siRNAs involves the noncanonical, concerted action of RNA POLYMERASE IV, RNA-DEPENDENT RNA POLYMERASE-2, and DICER-LIKE-4. Furthermore, the chromatin association/dissociation of the DDB2-AGO1 complex is under the control of siRNA abundance and DNA damage signaling. These findings reveal unexpected nuclear functions for DCL4 and AGO1, and shed light on the interplay between small RNAs and DNA repair recognition factors at damaged sites.

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Section: A Model For Dna Repair Mediated By Uvirnas and Their Possiblementioning

confidence: 99%

Small RNA-mediated repair of UV-induced DNA lesions by the DNA DAMAGE-BINDING PROTEIN 2 and ARGONAUTE 1

Schalk

Cognat

Graindorge

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…However, unresolved damage-induced transcription arrest triggers cell death [85]. To make matters worse, bypass of DNA lesions in the transcribed strand can cause transcriptional mutagenesis [86][87]. No specific translesion RNAPs are known to bypass helix distorting adducts.…”

Section: Tcr In Human Cellsmentioning

confidence: 99%

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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“…The integrity of genomic DNA constantly faces numerous attacks from both endogenous and environmental agents, some of which cause significant structural and chemical alterations to DNA (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). These DNA lesions, when situated in actively transcribed genomic regions, can significantly perturb pol IIcatalyzed transcriptional elongation (1,5,6,(10)(11)(12)(13)(14)(15)(16).…”

mentioning

confidence: 99%

Mechanism of DNA alkylation-induced transcriptional stalling, lesion bypass, and mutagenesis

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Alkylated DNA lesions, induced by both exogenous chemical agents and endogenous metabolites, interfere with the efficiency and accuracy of DNA replication and transcription. However, the molecular mechanisms of DNA alkylation-induced transcriptional stalling and mutagenesis remain unknown. In this study, we systematically investigated how RNA polymerase II (pol II) recognizes and bypasses regioisomeric -,3-, and -ethylthymidine (-, 3-, and-EtdT) lesions. We observed distinct pol II stalling profiles for the three regioisomeric EtdT lesions. Intriguingly, pol II stalling at -EtdT and3-EtdT sites is exacerbated by TFIIS-stimulated proofreading activity. Assessment for the impact of the EtdT lesions on individual fidelity checkpoints provided further mechanistic insights, where the transcriptional lesion bypass routes for the three EtdT lesions are controlled by distinct fidelity checkpoints. The error-free transcriptional lesion bypass route is strongly favored for the minor-groove -EtdT lesion. In contrast, a dominant error-prone route stemming from GMP misincorporation was observed for the major-groove-EtdT lesion. For the 3-EtdT lesion that disrupts base pairing, multiple transcriptional lesion bypass routes were found. Importantly, the results from the present in vitro transcriptional studies are well correlated with in vivo transcriptional mutagenesis analysis. Finally, we identified a minor-groove-sensing motif from pol II (termed Pro-Gate loop). The Pro-Gate loop faces toward the minor groove of RNA:DNA hybrid and is involved in modulating the translocation of minor-groove alkylated DNA template after nucleotide incorporation opposite the lesion. Taken together, this work provides important mechanistic insights into transcriptional stalling, lesion bypass, and mutagenesis of alkylated DNA lesions.

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Molecular basis of transcriptional fidelity and DNA lesion-induced transcriptional mutagenesis

Cited by 28 publications

References 169 publications

Small RNA-mediated repair of UV-induced DNA lesions by the DNA DAMAGE-BINDING PROTEIN 2 and ARGONAUTE 1

Small RNA-mediated repair of UV-induced DNA lesions by the DNA DAMAGE-BINDING PROTEIN 2 and ARGONAUTE 1

Mechanistic insights into transcription coupled DNA repair

Mechanism of DNA alkylation-induced transcriptional stalling, lesion bypass, and mutagenesis

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