A Molecular Basis for Damage Recognition in Eukaryotic Nucleotide Excision Repair

Schärer, Orlando D.

doi:10.1002/cbic.200700619

Cited by 13 publications

(15 citation statements)

References 51 publications

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“…Such DNA damage is detected in two ways: 1) the global-genome NER (GG-NER) sub-pathway, which detects lesions with sufficient helix-opening properties anywhere in the genome, and 2) the transcription-coupled NER (TC-NER) sub-pathway, which is selective for lesions that stall the transcription elongation machinery. Both processes detect lesions in a different manner, but the repair process uses the same toolbox, which opens the helix, excises a 22–30-base damage-containing oligonucleotide, fills in the single-strand gap by repair synthesis and ligates the final nick 27 .…”

Section: Insights From Dna Repair-deficient Progeroid Human Syndromesmentioning

confidence: 99%

DNA damage and ageing: new-age ideas for an age-old problem

et al. 2008

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Loss of genome maintenance may causally contribute to ageing, as exemplified by the premature appearance of multiple symptoms of ageing in a growing family of human syndromes and in mice with genetic defects in genome maintenance pathways. Recent evidence revealed a similarity between such prematurely ageing mutants and long-lived mice harbouring mutations in growth signalling pathways. At first sight this seems paradoxical as they represent both extremes of ageing yet show a similar ‘survival’ response that is capable of delaying age-related pathology and extending lifespan. Understanding the mechanistic basis of this response and its connection with genome maintenance would open exciting possibilities for counteracting cancer or age-related diseases, and for promoting longevity.

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Section: Insights From Dna Repair-deficient Progeroid Human Syndromesmentioning

confidence: 99%

DNA damage and ageing: new-age ideas for an age-old problem

et al. 2008

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“…However, regardless of exactly what these distortions are, we hypothesize that they must provide a local thermodynamic destabilization signal for repair to ensue, and the greater the extent of destabilization, the better the repair. The destabilization would facilitate the strand separation, base-flipping, and β -hairpin insertion by the XPC/HR23B recognition factor [41, 73] needed to initiate NER. In this way, the NER machinery would excise a large variety of lesions with different efficiencies, by recognizing the thermodynamic impact of the lesions rather than the lesions themselves [24, 29, 41, 73].…”

Section: Understanding Repairability Differences: the Degree Of Lomentioning

confidence: 99%

Base Sequence Context Effects on Nucleotide Excision Repair

Cai

Patel

Broyde

et al. 2010

Journal of Nucleic Acids

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Nucleotide excision repair (NER) plays a critical role in maintaining the integrity of the genome when damaged by bulky DNA lesions, since inefficient repair can cause mutations and human diseases notably cancer. The structural properties of DNA lesions that determine their relative susceptibilities to NER are therefore of great interest. As a model system, we have investigated the major mutagenic lesion derived from the environmental carcinogen benzo[a]pyrene (B[a]P), 10S (+)-trans-anti-B[a]P-N2-dG in six different sequence contexts that differ in how the lesion is positioned in relation to nearby guanine amino groups. We have obtained molecular structural data by NMR and MD simulations, bending properties from gel electrophoresis studies, and NER data obtained from human HeLa cell extracts for our six investigated sequence contexts. This model system suggests that disturbed Watson-Crick base pairing is a better recognition signal than a flexible bend, and that these can act in concert to provide an enhanced signal. Steric hinderance between the minor groove-aligned lesion and nearby guanine amino groups determines the exact nature of the disturbances. Both nearest neighbor and more distant neighbor sequence contexts have an impact. Regardless of the exact distortions, we hypothesize that they provide a local thermodynamic destabilization signal for repair.

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“…These structural findings are particularly intriguing because they suggest that thermodynamic destabilization of the native B-DNA structure can play an important role [29, 30] in the recognition of DNA lesions in both NER systems, a concept that had been previously proposed [4, 31–33]. …”

Section: Introductionmentioning

confidence: 99%

“…The insertion of β-hairpins between the lesion-containing and undamaged complementary strand should be more facile in the case of lesions that cause significant local destabilization of DNA duplexes, and more difficult in the case of lesions that do not (see also review by Fuss and Tainer in this issue of DNA Repair). These considerations suggest that the thermodynamic properties of the lesions are in some way correlated with NER efficiencies in both systems [29, 30]. In order to test this hypothesis we have analyzed a series of defined substrates by the prokaryotic and eukaryotic NER systems.…”

Section: Introductionmentioning

confidence: 99%

Probing for DNA damage with β-hairpins: Similarities in incision efficiencies of bulky DNA adducts by prokaryotic and human nucleotide excision repair systems in vitro

et al. 2011

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Nucleotide excision repair (NER) is an important prokaryotic and eukaryotic defense mechanism that removes a large variety of structurally distinct lesions in cellular DNA. While the proteins involved are completely different, the mode of action of these two repair systems is similar, involving a cut-and-patch mechanism in which an oligonucleotide sequence containing the lesion is excised. The prokaryotic and eukaryotic NER damage-recognition factors have common structural features of β-hairpin intrusion between the two DNA strands at the site of the lesion. In the present study, we explored the hypothesis that this common β-hairpin intrusion motif is mirrored in parallel NER incision efficiencies in the two systems. We have utilized human HeLa cell extracts and the prokaryotic UvrABC proteins to determine their relative NER incision efficiencies. We report here comparisons of relative NER efficiencies with a set of stereoisomeric DNA lesions derived from metabolites of benzo[a]pyrene and equine estrogens in different sequence contexts, utilizing 21 samples. We found a general qualitative trend towards similar relative NER incision efficiencies for ~ 65% of these substrates; the other cases deviate mostly by ~ 30% or less from a perfect correlation, although several more distant outliers are also evident. This resemblance is consistent with the hypothesis that lesion recognition through β-hairpin insertion, a common feature of the two systems, is facilitated by local thermodynamic destabilization induced by the lesions in both cases. In the case of the UvrABC system, varying the nature of the UvrC endonuclease, while maintaining the same UvrA/B proteins, can markedly affect the relative incision efficiencies. These observations suggest that, in addition to recognition involving the initial modified duplexes, downstream events involving UvrC can also play a role in distinguishing and processing different lesions in prokaryotic NER.

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A Molecular Basis for Damage Recognition in Eukaryotic Nucleotide Excision Repair

Cited by 13 publications

References 51 publications

DNA damage and ageing: new-age ideas for an age-old problem

DNA damage and ageing: new-age ideas for an age-old problem

Base Sequence Context Effects on Nucleotide Excision Repair

Probing for DNA damage with β-hairpins: Similarities in incision efficiencies of bulky DNA adducts by prokaryotic and human nucleotide excision repair systems in vitro

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