Strand-specific Recognition of DNA Damages by XPD Provides Insights into Nucleotide Excision Repair Substrate Versatility

Buechner, Claudia N.; Heil, Korbinian; Michels, G.; Carell, Thomas; Kisker, Caroline; Teßmer, Ingrid

doi:10.1074/jbc.m113.523001

Cited by 43 publications

(64 citation statements)

References 47 publications

(55 reference statements)

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“…Using atomic force microscopy (AFM) imaging, we could recently show that archaeal XPD exploits its helicase activity using different approaches for damage recognition depending on the type of lesion (12). Specifically, we observed distinct DNA strand preferences indicating different strategies for verification, as may serve to support the vast spectrum of NER targets.…”

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“…Specifically, we observed distinct DNA strand preferences indicating different strategies for verification, as may serve to support the vast spectrum of NER targets. Our studies further revealed conformational changes in the specific XPD-lesion complexes (12). Such structural rearrangements may serve to trigger the recruitment of additional proteins, including the two endonucleases (XPG and XPF) in eukaryotic NER, resulting in the excision of a 24 -32-nt stretch containing the lesion, and finally DNA re-synthesis and ligation by DNA polymerase and ligase, respectively (2).…”

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confidence: 99%

“…Many of the mechanistic steps also show strong parallels such as the initial ATP-independent sensing of DNA helix distortions by UvrA (14) and XPC (15), or the ATP re-binding induced conformational changes necessary for the formation of a stable lesion-specific complex by UvrB (16,17) and (archaeal) XPD (12).…”

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Conservation and Divergence in Nucleotide Excision Repair Lesion Recognition

Wirth

Gross

Roth

et al. 2016

Journal of Biological Chemistry

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Nucleotide excision repair is an important and highly conserved DNA repair mechanism with an exceptionally large range of chemically and structurally unrelated targets. Lesion verification is believed to be achieved by the helicases UvrB and XPD in the prokaryotic and eukaryotic processes, respectively. Using single molecule atomic force microscopy analyses, we demonstrate that UvrB and XPD are able to load onto DNA and pursue lesion verification in the absence of the initial lesion detection proteins. Interestingly, our studies show different lesion recognition strategies for the two functionally homologous helicases, as apparent from their distinct DNA strand preferences, which can be rationalized from the different structural features and interactions with other nucleotide excision repair protein factors of the two enzymes. Nucleotide excision repair (NER)4 is an important DNA repair mechanism with a large range of chemically and structurally unrelated targets. Examples range from bulky DNA adducts to interstrand DNA cross-links caused by antitumor drugs (1-3). In humans, NER is the only repair system for the removal of UV irradiation-induced photoproducts such as the intrastrand cross-linking cyclobutane-pyrimidine dimers (CPDs), and dysfunctional NER is responsible for severe diseases, including xeroderma pigmentosum (XP) (1-3).The mechanism of NER is highly conserved between organisms. In bacteria, NER involves the proteins UvrA, UvrB, and UvrC. In the current model of prokaryotic NER, a hetero-tetrameric complex of UvrA and UvrB (UvrA 2 B 2 ) scans the DNA for lesions. When a lesion is encountered, initial lesion sensing by a dimer of UvrA is based on detection of DNA distortion. Conformational changes in the UvrA 2 B 2 complex result in an unwinding and opening of dsDNA around the lesion, providing an unpaired (bubble) region likely required by UvrB to thread onto one of the ssDNA strands. The helicase UvrB is believed to verify the presence of a lesion by insertion of a ␤-hairpin via interactions with residues at the base of the hairpin (2). Upon lesion verification by UvrB, UvrA dissociates from the complex, and ATP re-binding by UvrB results in the formation of the lesion-specific UvrB-DNA complex, which recruits the NER endonuclease UvrC (UvrBC complex). UvrC carries out two incisions on either side of the lesion. The 12-13-nucleotide (nt)-long ssDNA stretch (2) containing the lesion can then be removed together with the endonuclease by the helicase UvrD, and the resulting gap is filled and sealed by DNA polymerase I and ligase.Eukaryotic NER encompasses a total of ϳ30 proteins, including the xeroderma pigmentosum group proteins (XPA-XPG). Repair can either be initiated by a stalled RNA polymerase in transcription-coupled NER or via global genome NER. In global genome NER, upon initial detection of short destabilized DNA structures by the CEN2-XPC-HR23B complex, the ATPase/ helicase XPB, which is part of the 10-subunit transcription factor IIH (TFIIH) complex, then directly interacts with XPC (4) and...

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Conservation and Divergence in Nucleotide Excision Repair Lesion Recognition

Wirth

Gross

Roth

et al. 2016

Journal of Biological Chemistry

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“…S2). The affinity of the proteins toward the UAS DNA was measured by biolayer interferometry (52,53) at both 30°C and 37°C. The traces were fit to a 1:1 Langmuir interaction model to estimate the approximate binding affinities (Table 1 and Fig.…”

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Rational elicitation of cold-sensitive phenotypes

Baliga

Majhi

Mondal

et al. 2016

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

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Cold-sensitive phenotypes have helped us understand macromolecular assembly and biological phenomena, yet few attempts have been made to understand the basis of cold sensitivity or to elicit it by design. We report a method for rational design of cold-sensitive phenotypes. The method involves generation of partial loss-of-function mutants, at either buried or functional sites, coupled with selective overexpression strategies. The only essential input is amino acid sequence, although available structural information can be used as well. The method has been used to elicit cold-sensitive mutants of a variety of proteins, both monomeric and dimeric, and in multiple organisms, namely Escherichia coli, Saccharomyces cerevisiae, and Drosophila melanogaster. This simple, yet effective technique of inducing cold sensitivity eliminates the need for complex mutations and provides a plausible molecular mechanism for eliciting cold-sensitive phenotypes.conditional mutants | rational design | cold sensitivity | heat-induced expression | transfer between organisms C onditional mutants are powerful tools for studying gene function in vivo. A conditional mutant retains the function of a gene under one set of conditions, called permissive, and lacks that function under a different set of conditions, called restrictive, whereas the wild type (WT) phenotype is similar across both conditions. Cold-sensitive (cs) mutants behave like loss-of-function mutants at temperatures lower than a cutoff temperature, but have WT-like phenotypes at higher temperatures. In contrast, temperature-sensitive (ts) mutants show heat sensitivity and behave like the WT below the restrictive temperature. Both cs and ts mutants can provide important information about protein structure, function, and assembly. cs mutants are rarer than ts mutants, and the molecular basis for generation of cs phenotypes is currently unclear.cs mutants have been used to analyze various biological phenomena, most commonly the cell cycle (1-3), ribosome assembly (4-8), and protein export (9-11), as well as to understand macromolecular structure-function relationships (12, 13). Various ts and cs variants also have helped us understand P22 phage coat protein assembly. Using a combination of both ts and cs mutants causing defects at different stages of the assembly pathway, the order of the various steps occurring along this pathway has been determined (14). Thus, these conditional mutants have led to a greater understanding of phage genetics, protein folding, and macromolecular assembly (15)(16)(17). Similarly, cs and ts mutants of different genes essential for cell division, in combination with temperature-shift experiments, have been used to understand the cell cycle phases in which each of these genes act (18).Various changes at the amino acid level or gene regulation level can cause cold sensitivity. Some cs mutants have been suggested to result from altered feedback inhibition of certain metabolic pathways at lower temperatures (19,20). Cold sensitivity also has been attribut...

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“…Também participa do reconhecimento da lesão (Yokoi et al, 2000), através de diferentes mudanças na conformação da proteína XPD (Buechner et al, 2014). Na transcrição, após o posicionamento do complexo de pré-iniciação (TFIIA, TFIIB, TFIID, TFIIE, TFIIF e na RNA polimerase II), TFIIH é responsável pela abertura da dupla fita na região próxima ao promotor, através da atividade de helicase de XPB (Holstege et al, 1996), além de fosforilar o domínio C-terminal da RNA pol II através da atividade de quinase de CDK7 (Feaver et al, 1991); essa fosforilação é necessária para evitar o bloqueio do complexo no promotor e para o início da transcrição (Dvir et al, 1997).…”

Section: Mutações Em Xpd/ercc2unclassified

Papel das proteínas XPD e DNA polimerase eta nas respostas de células humanas a danos no genoma

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Strand-specific Recognition of DNA Damages by XPD Provides Insights into Nucleotide Excision Repair Substrate Versatility

Cited by 43 publications

References 47 publications

Conservation and Divergence in Nucleotide Excision Repair Lesion Recognition

Conservation and Divergence in Nucleotide Excision Repair Lesion Recognition

Rational elicitation of cold-sensitive phenotypes

Papel das proteínas XPD e DNA polimerase eta nas respostas de células humanas a danos no genoma

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