TFIIH-p52ΔC defines a ninth xeroderma pigmentosum complementation–group XP-J and restores TFIIH stability to p8-defective trichothiodystrophy
Yuka Nakazawa, Lin Ye, Yasuyoshi Oka, Hironobu Morinaga, Kana Kato, Mayuko Shimada, Kotaro Tsukada, Koyo Tsujikawa, Yosuke Nishio, Hiva Fassihi, Shehla Mohammed, Alan R. Lehmann, Tomoo Ogi
Yuka Nakazawa, Lin Ye, Yasuyoshi Oka, Hironobu Morinaga, Kana Kato, Mayuko Shimada, Kotaro Tsukada, Koyo Tsujikawa, Yosuke Nishio, Hiva Fassihi, Shehla Mohammed, Alan R. Lehmann, Tomoo Ogi
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Research Article Cell biology Dermatology Genetics

TFIIH-p52ΔC defines a ninth xeroderma pigmentosum complementation–group XP-J and restores TFIIH stability to p8-defective trichothiodystrophy

Abstract

Few drugs are available for rare diseases due to economic disincentives. However, tailored medications for extremely rare disorders (N-of-1) offer a ray of hope. Artificial antisense oligonucleotides (ASOs) are now best known for their use in spinal muscular atrophy (SMA). The success of nusinersen/Spinraza for SMA indicates the potential of ASO therapies for other rare conditions. We propose a strategy to develop N-of-1 ASOs for treating one form of trichothiodystrophy (TTD), a rare condition with multisystem abnormalities and reduced life expectancy, associated with instability and greatly reduced amounts of the DNA-repair/transcription factor TFIIH. The therapeutic targets carry mutations in GTF2H5, encoding the TFIIH-p8 subunit. This approach was inspired by the diagnosis and molecular dissection of a xeroderma pigmentosum (XP) case with mutations in GTF2H4, encoding the TFIIH-p52 subunit. This is newly classified as a ninth XP complementation–group, XP-J, identified 5 decades after the discovery of the other XP complementation–groups. The p8-p52 interaction is required to support the TFIIH-complex formation, and the patient’s p52 C-terminal truncation results in the complete absence of p8 in TFIIH. However, intriguingly, TFIIH remained stable in vivo, and the patient with XP-J did not exhibit any TTD-features. The aim of our ASO-design is to induce a C-terminal truncation of p52 and we have successfully stabilized TFIIH in p8-deficient cells from patients with TTD-A.

Authors

Yuka Nakazawa, Lin Ye, Yasuyoshi Oka, Hironobu Morinaga, Kana Kato, Mayuko Shimada, Kotaro Tsukada, Koyo Tsujikawa, Yosuke Nishio, Hiva Fassihi, Shehla Mohammed, Alan R. Lehmann, Tomoo Ogi

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Figure 5

A model for the p52 C-terminal self-inhibitory structure.

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A model for the p52 C-terminal self-inhibitory structure. (A) The full l...
(A) The full length p52 forms a homodimer or adopts an autoinhibited monomer (p52’). Prior structural conversion of p52-p52 dimer or p52’, mediated by the p52-p8 interaction, is required for the formation of the TFIIH complex. (B and C) AlphaFold structure prediction revealed a potential homodimer formation mediated by the C-terminal domain of p52. In the rank1 model, the relative positioning of the C-terminal domains of molecule A and molecule B appears to be fixed (blue) (B). p52 monomer, shown in blue (top-left: C-terminal domain, white), and p52-p8 dimer (top-right: p8, yellow) in the cryo-EM TFIIH structure, pdb:8ebt (55). Full-length p52 homodimer structure, with N-terminal steric crashes, predicted in B (bottom-left: first p52 molecule, blue; second p52 molecule, N-terminal domain, sky blue/C-terminal domain, yellow-green). p52 C-terminal domain (401-462aa) homodimer structure (bottom-middle: first molecule, white; second molecule, yellow-green), and the relative positioning (bottom-right: fixed positions shown in blue) (C). (D) Crystal structure of a fungal p52-p8 (pdb: 6trs) (64). C-terminal domain of the second p52 molecule lacks electron density. (E) A model showing ASO-mediated conversion from TTD-A (severe clinical manifestations) to XP-J (a milder disorder).