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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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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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].”
From Sunlight damage to cellular DNA: focus on oxidatively generated lesions (2017) · cites this paper as [241]
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Self-citation
- 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
- PMC
- PMC3234290
- 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
- green
- www.ncbi.nlm.nih.gov
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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