Cited by 369DNA Repair MechanismsEnzyme Structure and FunctionProtein Structure and Dynamics

XPD Helicase Structures and Activities: Insights into the Cancer and Aging Phenotypes from XPD Mutations

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Fan, Li, Fuss, Jill O., Cheng, Quen J., Arvai, Andrew S., Hammel, Michal, Roberts, Victoria A., Cooper, Priscilla K., Tainer, John A.·2008·Cell

Abstract

Mutations in XPD helicase, required for nucleotide excision repair (NER) as part of the transcription/repair complex TFIIH, cause three distinct phenotypes: cancer-prone xeroderma pigmentosum (XP), or aging disorders Cockayne syndrome (CS), and trichothiodystrophy (TTD). To clarify molecular differences underlying these diseases, we determined crystal structures of the XPD catalytic core from Sulfolobus acidocaldarius and measured mutant enzyme activities. Substrate-binding grooves separate adjacent Rad51/RecA-like helicase domains (HD1, HD2) and an arch formed by 4FeS and Arch domains. XP mutations map along the HD1 ATP-binding edge and HD2 DNA-binding channel and impair helicase activity essential for NER. XP/CS mutations both impair helicase activity and likely affect HD2 functional movement. TTD mutants lose or retain helicase activity but map to sites in all four domains expected to cause framework defects impacting TFIIH integrity. These results provide a foundation for understanding disease consequences of mutations in XPD and related 4Fe-4S helicases including FancJ.

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Crossref · 10.1016/j.cell.2008.04.030

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  • Mutations in the XPD helicase can cause at least three disease states: xeroderma pigmentosa, Cockayne syndrome, and trichothiodystrophy.

    “Mutations in the xeroderma pigmentosa helicase XPD can lead to at least three disease states including xeroderma pigmentosa, Cockayne syndrome and trichothiodystrophy [81].”

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Authors
Fan, L., Fuss, J. O., Cheng, Q. J., Arvai, A. S., Hammel, M., Roberts, V. A., Cooper, P. K., & Tainer, J. A.
Affiliations
  • Scripps Research Institute (US)
  • Lawrence Berkeley National Laboratory (US)
  • San Diego Supercomputer Center (US)
Corresponding author
Tainer, John A.
Venue
Cell
Publisher
Elsevier BV
Published
2008-05
Volume
133
Issue
5
Pages
789-800
ISSN
0092-8674 (ISSN-L)
OpenAlex
W2114382972
Cited by
369
References
48
Citations by year
2026: 9 · 2025: 11 · 2024: 6 · 2023: 10 · 2022: 12 · 2021: 18 · 2020: 21 · 2019: 20 · 2018: 19 · 2017: 16 · 2016: 26 · 2015: 32 · 2014: 26 · 2013: 26 · 2012: 35
FWCI
11.15
Type
journal article
Language
en
Open access
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
  • University of North Texas Digital Library (University of North Texas) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (R01CA112093, F32CA108393, P01CA092584)
  • National Institute of General Medical Sciences (R01GM070996, GM070996)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
XPD helicase, nucleotide excision repair, TFIIH, xeroderma pigmentosum, Cockayne syndrome, trichothiodystrophy, crystal structure, Sulfolobus acidocaldarius, helicase activity, ATP-binding domain, aging, cancer susceptibility, FANCJ
MeSH terms
Cockayne Syndrome, DNA Repair, DNA Helicases, Iron-Sulfur Proteins, Models, Molecular, Mutation, Xeroderma Pigmentosum, Sulfolobus acidocaldarius, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Crystallography, X-Ray, Archaeal Proteins, Structural Homology, Protein, Xeroderma Pigmentosum Group D Protein, Trichothiodystrophy Syndromes

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