A new structural insight into XPA–DNA interactions
Open accessAbstract
XPA (xeroderma pigmentosum group A) protein is an essential factor for NER (nucleotide excision repair) which is believed to be involved in DNA damage recognition/verification, NER factor recruiting and stabilization of repair intermediates. Past studies on the structure of XPA have focused primarily on XPA interaction with damaged DNA. However, how XPA interacts with other DNA structures remains unknown though recent evidence suggest that these structures could be important for its roles in both NER and non-NER activities. Previously, we reported that XPA recognizes undamaged DNA ds/ssDNA (double-strand/single-strandDNA) junctions with a binding affinity much higher than its ability to bind bulky DNA damage. To understand how this interaction occurs biochemically we implemented a structural determination of the interaction using a MS-based protein footprinting method and limited proteolysis. By monitoring surface accessibility of XPA lysines to NHS-biotin modification in the free protein and the DNA junction-bound complex we show that XPA physically interacts with the DNA junctions via two lysines, K168 and K179, located in the previously known XPA(98–219) DBD (DNA-binding domain). Importantly, we also uncovered new lysine residues, outside of the known DBD, involved in the binding. We found that residues K221, K222, K224 and K236 in the C-terminal domain are involved in DNA binding. Limited proteolysis analysis of XPA–DNA interactions further confirmed this observation. Structural modelling with these data suggests a clamp-like DBD for the XPA binding to ds/ssDNA junctions. Our results provide a novel structure-function view of XPA–DNA junction interactions.
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Hilton et al. showed that XPA uses a larger DNA-binding domain for ds-ssDNA junctions than was previously described for repair substrates.
“Hilton et al. recently demonstrated that in binding to ds-ssDNA junctions XPA employs a larger DNA-binding domain 102 than was previously described for repair substrates 103, 104.”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [102]
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XPA: A key scaffold for human nucleotide excision repair
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Self-citation
- Authors
- Hilton, B., Shkriabai, N., Musich, P. R., Kvaratskhelia, M., Shell, S., & Zou, Y.
- Affiliations
- East Tennessee State University (US)
- The Ohio State University (US)
- Vanderbilt University (US)
- Corresponding author
- Hilton, Benjamin
- Zou, Yue
- Venue
- Bioscience Reports
- Publisher
- Portland Press Ltd.
- Published
- 2014-12-01
- Volume
- 34
- Issue
- 6
- Pages
- e00162-e00162
- ISSN
- 0144-8463 (ISSN-L)
- 1573-4935
- PMC
- PMC4266923
- OpenAlex
- W2030896917
- Cited by
- 22
- References
- 44
- Citations by year
- 2022: 1 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 3 · 2017: 8 · 2016: 3 · 2015: 1
- FWCI
- 1.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Bioscience Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons - East Tennessee State University (East Tennessee State University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Cancer Institute (R01CA086927, CA-86927)
- National Institute of Allergy and Infectious Diseases (R01AI062520)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- XPA, nucleotide excision repair, DNA junctions, DNA-binding domain, lysine residues, C-terminal domain, protein-DNA interactions, DNA damage recognition, protein structure-function relationship
- MeSH terms
- Base Sequence, Binding Sites, DNA, DNA-Binding Proteins, Humans, Lysine, Models, Molecular, Molecular Sequence Data, Nucleic Acid Conformation, Protein Binding, Protein Structure, Tertiary, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Xeroderma Pigmentosum Group A Protein, Proteolysis
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