2018
DOI: 10.1021/acs.chemrestox.8b00231
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Lesion Sensing during Initial Binding by Yeast XPC/Rad4: Toward Predicting Resistance to Nucleotide Excision Repair

Abstract: Nucleotide excision repair (NER) excises a variety of environmentally derived DNA lesions. However, NER efficiencies for structurally different DNA lesions can vary by orders of magnitude; yet the origin of this variance is poorly understood. Our goal is to develop computational strategies that predict and identify the most hazardous, repair-resistant lesions from the plethora of such adducts. In the present work, we are focusing on lesion recognition by the xeroderma pigmentosum C protein complex (XPC), the f… Show more

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Cited by 20 publications
(32 citation statements)
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References 45 publications
(137 reference statements)
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“…Rad4 could take advantage of and amplify the intrinsically higher distortion/distort-ability and weaker van der Waals stacking energy in the CCC/GGG sequence. In general, the untwisting of the DNA duplex and the engagement of BHD2 shown with the CCC/GGG sequence recapitulates the features previously shown with NER-proficient lesions (7,30). However, unlike the bona fide NER lesions such as 6-4PP or dibenzo[a,l]pyrenederived dG lesion, we did not observe partner base flipping for CCC/GGG, which indicates that the kinetics of DNA opening for the more stable, matched DNA must be slower than those of the 6-4PP lesion.…”
Section: Furthermore Ccc/ggg Was Bent In a Direction That Is Consistsupporting
confidence: 72%
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“…Rad4 could take advantage of and amplify the intrinsically higher distortion/distort-ability and weaker van der Waals stacking energy in the CCC/GGG sequence. In general, the untwisting of the DNA duplex and the engagement of BHD2 shown with the CCC/GGG sequence recapitulates the features previously shown with NER-proficient lesions (7,30). However, unlike the bona fide NER lesions such as 6-4PP or dibenzo[a,l]pyrenederived dG lesion, we did not observe partner base flipping for CCC/GGG, which indicates that the kinetics of DNA opening for the more stable, matched DNA must be slower than those of the 6-4PP lesion.…”
Section: Furthermore Ccc/ggg Was Bent In a Direction That Is Consistsupporting
confidence: 72%
“…However, unlike the bona fide NER lesions such as 6-4PP or dibenzo[a,l]pyrenederived dG lesion, we did not observe partner base flipping for CCC/GGG, which indicates that the kinetics of DNA opening for the more stable, matched DNA must be slower than those of the 6-4PP lesion. On the other hand, the stronger stacking for the CGC/GCG duplex supported the stability of its DNA even in the presence of WT Rad4, consistent with its failure to untwist and engage with the BHD2 hairpin in the minor groove, features which were also characteristic of NER-impaired/resistant lesions such as CPD (7,30). As a result of these localized structural and energetic properties in the CGC/GCG duplex, the potential 'open' site is not sensed nor further processed by the BHD2 and BHD3 domains, thus congruent with its reverse-mode crystal structure showing 'closed' DNA.…”
Section: Furthermore Ccc/ggg Was Bent In a Direction That Is Consistmentioning
confidence: 95%
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“…Base-displaced intercalated conformers have been shown to facilitate Rad4 recognition in computational and experimental work [71][72] . Computational studies have revealed that the displaced partner base in the case of the NER-proficient (+) cis-benzo[a]pyrene-dG adduct is readily captured by a pocket between BHD2 and BHD3 while the BHD2 hairpin binds into the minor groove and untwists the duplex; in contrast, these structural hallmarks of initial lesion recognition by Rad4 are missing when the partner nucleotide is absent, in which case the lesion becomes NER-resistant 72 .…”
Section: Discussionmentioning
confidence: 99%
“…The average FRET efficiency for each sample Figure S10. The BHD2 occupied AlphaSpace of the DNA minor groove was measured as previously described (25,41) to reflect the extent of BHD2 binding. Base extrusion for the potential flipping nucleotides (dC's in W16-17, Figure 2A) was measured using a pseudo-dihedral angle ( Figure S11).…”
Section: Synthesis Of Oligonucleotides and Preparation Of Duplex Dnamentioning
confidence: 99%