Cited by 170DNA Repair MechanismsGenomics and Chromatin DynamicsProtein Structure and Dynamics

XPB and XPD helicases in TFIIH orchestrate DNA duplex opening and damage verification to coordinate repair with transcription and cell cycle via CAK kinase

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Fuss, Jill O., Tainer, John A.·2011·DNA Repair

Abstract

Helicases must unwind DNA at the right place and time to maintain genomic integrity or gene expression. Biologically critical XPB and XPD helicases are key members of the human TFIIH complex; they anchor CAK kinase (cyclinH, MAT1, CDK7) to TFIIH and open DNA for transcription and for repair of duplex distorting damage by nucleotide excision repair (NER). NER is initiated by arrested RNA polymerase or damage recognition by XPC-RAD23B with or without DDB1/DDB2. XP helicases, named for their role in the extreme sun-mediated skin cancer predisposition xeroderma pigmentosum (XP), are then recruited to asymmetrically unwind dsDNA flanking the damage. XPB and XPD genetic defects can also cause premature aging with profound neurological defects without increased cancers: Cockayne syndrome (CS) and trichothiodystrophy (TTD). XP helicase patient phenotypes cannot be predicted from the mutation position along the linear gene sequence and adjacent mutations can cause different diseases. Here we consider the structural biology of DNA damage recognition by XPC-RAD23B, DDB1/DDB2, RNAPII, and ATL, and of helix unwinding by the XPB and XPD helicases plus the bacterial repair helicases UvrB and UvrD in complex with DNA. We then propose unified models for TFIIH assembly and roles in NER. Collective crystal structures with NMR and electron microscopy results reveal functional motifs, domains, and architectural elements that contribute to biological activities: damaged DNA binding, translocation, unwinding, and ATP driven changes plus TFIIH assembly and signaling. Coupled with mapping of patient mutations, these combined structural analyses provide a framework for integrating and unifying the rich biochemical and cellular information that has accumulated over forty years of study. This integration resolves puzzles regarding XP helicase functions and suggests that XP helicase positions and activities within TFIIH detect and verify damage, select the damaged strand for incision, and coordinate repair with transcription and cell cycle through CAK signaling.

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Crossref · 10.1016/j.dnarep.2011.04.028

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  • Mutations on XPB or XPD that destabilize TFIIH generally lead to cell death and tissue degeneration, whereas mutations that cause defects in helicase or ATPase activities disrupt repair and lead to cancer.

    “Therefore, mutations on XPB or XPD that destabilize TFIIH generally lead to cell death and tissue degeneration whereas mutations that cause defects in the helicase or ATPase activities disrupt repair and lead to cancer [241].”

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Authors
Fuss, J. O., & Tainer, J. A.
Affiliations
  • Lawrence Berkeley National Laboratory (US)
  • Scripps Research Institute (US)
Corresponding author
  • Fuss, Jill O.
  • Tainer, John A.
Venue
DNA Repair
Publisher
Elsevier BV
Published
2011-07
Volume
10
Issue
7
Pages
697-713
ISSN
  • 1568-7856 (ISSN-L)
  • 1568-7864
OpenAlex
W1977449047
Cited by
170
References
185
Citations by year
2026: 5 · 2025: 8 · 2024: 8 · 2023: 8 · 2022: 5 · 2021: 11 · 2020: 11 · 2019: 8 · 2018: 13 · 2017: 14 · 2016: 14 · 2015: 14 · 2014: 15 · 2013: 19 · 2012: 13
FWCI
1.48
Type
journal article
Language
en
Open access
Locations
  • DNA repair (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (R01CA112093, CA112093)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
XPB helicase, XPD helicase, TFIIH, nucleotide excision repair, DNA damage recognition, RNA polymerase II, UvrB, UvrD, xeroderma pigmentosum, Cockayne syndrome, trichothiodystrophy, transcription-coupled repair, cell cycle checkpoints, helicase translocation
MeSH terms
Cyclin-Dependent Kinase-Activating Kinase, Adenosine Triphosphate, Bacterial Proteins, Cell Cycle, DNA, DNA Damage, DNA Repair, DNA-Binding Proteins, Humans, Models, Molecular, Transcription, Genetic, Xeroderma Pigmentosum, Signal Transduction, Protein Structure, Tertiary, Cyclin-Dependent Kinases, Catalytic Domain, DNA Repair Enzymes, Transcription Factor TFIIH, Xeroderma Pigmentosum Group D Protein

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