Structure and mechanism of the UvrA–UvrB DNA damage sensor

Pakotiprapha, Danaya; Samuels, Martin A.; Shen, Koning; Hu, Johnny H.; Jeruzalmi, David

doi:10.1038/nsmb.2240

Cited by 71 publications

(133 citation statements)

References 60 publications

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“…UvrABC were purified as described in ref. 49. Products of all reactions were separated in 6–23% denaturing polyacrylamide gels and visualized via phosphor-imaging using a Typhoon phosphor-imager (GE Healthcare) and Image Quant software (GE Healthcare).…”

Section: Methodsmentioning

confidence: 99%

UvrD facilitates DNA repair by pulling RNA polymerase backwards

Epshtein

Kamarthapu

McGary

et al. 2014

Nature

209

304

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UvrD helicase is required for nucleotide excision repair, although its role in this process is not well defined. Here we show that Escherichia coli UvrD binds RNA polymerase during transcription elongation and, using its helicase/translocase activity, forces RNA polymerase to slide backward along DNA. By inducing backtracking, UvrD exposes DNA lesions shielded by blocked RNA polymerase, allowing nucleotide excision repair enzymes to gain access to sites of damage. Our results establish UvrD as a bona fide transcription elongation factor that contributes to genomic integrity by resolving conflicts between transcription and DNA repair complexes. We further show that the elongation factor NusA cooperates with UvrD in coupling transcription to DNA repair by promoting backtracking and recruiting nucleotide excision repair enzymes to exposed lesions. Because backtracking is a shared feature of all cellular RNA polymerases, we propose that this mechanism enables RNA polymerases to function as global DNA damage scanners in bacteria and eukaryotes.

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Section: Methodsmentioning

confidence: 99%

UvrD facilitates DNA repair by pulling RNA polymerase backwards

Epshtein

Kamarthapu

McGary

et al. 2014

Nature

209

304

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show abstract

“…UvrA is suggested to be the first NER component that detect DNA lesion, but it's mechanism of DNA binding and damage recognition is not yet clear. NER is necessary for all organisms to eliminate DNA lesions (Pakotiprapha et al 2012). The fact that UvrA is associated with the bacterial surface is consistent with its action as a primary barrier for exogenous reactive molecules.…”

Section: Discussionmentioning

confidence: 70%

UvrA expression of Lactococcus lactis NZ9000 improve multiple stresses tolerance and fermentation of lactic acid against salt stress

Moghaddam

Zhang

2017

J Food Sci Technol

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Lactococcus lactis is subjected to several stressful conditions during industrial fermentation including oxidation, heating and cooling, acid, high osmolarity/ dehydration and starvation. DNA lesion is a major cause of genetic instability in L. lactis that usually occurs at a low frequency, but it is greatly enhanced by environmental stresses. DNA damages produced by these environmental stresses are thought to induce DNA double-strand breaks, leading to illegitimate recombination. Nucleotide excision repair (NER) protein UvrA suppresses multiple stressesinduced illegitimate recombination. UvrA protein can survive a coincident condition of environmental harsh conditions, multiple stress factors supposedly encountered in the host and inducing UvrA in L. lactis. In this study the expression of UvrA and growth performance and viability of control strain L. lactisVector and recombinant strain L. lactisUvrA under multiple stress conditions were determined. The recombinants strain had 30.70 and 52.67% higher growth performances when subjected to acidic and osmotic stresses conditions. In addition, the L. lactisUvrA strain showed 1.85-, 1.65-, and 2.40-fold higher biomass, lactate production, and lactate productivity, compared with the corresponding values for L. lactisVector strain during the osmotic stress. Results demonstrated NER system is involved in adaptation to various stress conditions and suggested that cells with a compromised UvrA as DNA repair system have an enhanced protection behavior in L. lactis NZ9000 against DNA damage.

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“…Alternatively, if Mfd does not detect the lesion itself, it might act by "feeding" DNA to repair proteins that are associated with it. A dimer of UvrA associated with Mfd is unlikely to be able to provide the observed strand specificity, because the dimer is symmetrical and is thought to probe both strands of DNA for damage simultaneously (14,15). The strand specificity could arise from the formation of an Mfd/UvrA 2 /UvrB complex at some point in the damage recognition process: Such a complex is likely to be able to load UvrB onto only one strand, and so lesions in the other strand would not be processed further.…”

Section: Discussionmentioning

confidence: 99%

“…During global NER, damage is detected by a search complex made up of a UvrA dimer and two molecules of the repair protein UvrB. Both partners contribute to lesion detection, and it is thought that a single heterotetramer simultaneously examines both strands of the DNA duplex for damage (14,15). Once a lesion is detected, a single UvrB remains stably bound at the site of damage.…”

mentioning

confidence: 99%

Stalled transcription complexes promote DNA repair at a distance

Haines

Kim

Smith

et al. 2014

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

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Transcription-coupled nucleotide excision repair (TCR) accelerates the removal of noncoding lesions from the template strand of active genes, and hence contributes to genome-wide variations in mutation frequency. Current models for TCR suppose that a lesion must cause RNA polymerase (RNAP) to stall if it is to be a substrate for accelerated repair. We have examined the substrate requirements for TCR using a system in which transcription stalling and damage location can be uncoupled. We show that Mfd-dependent TCR in bacteria involves the formation of a damage search complex that can detect lesions downstream of a stalled RNAP, and that the strand specificity of the accelerated repair pathway is independent of the requirement for a lesion to stall RNAP. We also show that an ops (operon polarity suppressor) transcription pause site, which causes backtracking of RNAP, can promote the repair of downstream lesions when those lesions do not themselves cause the polymerase to stall. Our findings indicate that the transcription-repair coupling factor Mfd, which is an ATP-dependent superfamily 2 helicase that binds to RNAP, continues to translocate along DNA after RNAP has been displaced until a lesion in the template strand is located. The discovery that pause sites can promote the repair of nonstalling lesions suggests that TCR pathways may play a wider role in modulating mutation frequencies in different parts of the genome than has previously been suspected.UvrA | DNA translocase | protein roadblock | ATPase

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Structure and mechanism of the UvrA–UvrB DNA damage sensor

Cited by 71 publications

References 60 publications

UvrD facilitates DNA repair by pulling RNA polymerase backwards

UvrD facilitates DNA repair by pulling RNA polymerase backwards

UvrA expression of Lactococcus lactis NZ9000 improve multiple stresses tolerance and fermentation of lactic acid against salt stress

Stalled transcription complexes promote DNA repair at a distance

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