Expanding the landscape of nucleotide excision repair disorders: from discovery to therapy
Arjan F. Theil, Jan H.J. Hoeijmakers
Arjan F. Theil, Jan H.J. Hoeijmakers
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Commentary

Expanding the landscape of nucleotide excision repair disorders: from discovery to therapy

Abstract

DNA damage and repair are central to the onset of cancer, aging, and aging-related diseases. Rare genetic defects in the nucleotide excision repair pathway, such as those causing the cancer-prone disorder xeroderma pigmentosum (XP) or the progeroid condition Cockayne syndrome, highlight the dramatic consequences of unrepaired DNA lesions. In this issue of the JCI, two related papers from Ogi and coworkers — Fassihi et al. and Nakazawa et al. — describe a new XP clinical entity, XP-J, linked to a pathogenic variant in the p52 subunit of the transcription-repair complex TFIIH. The studies’ characterization of XP-J and the p52ΔC variant opened unexpected possibilities to ameliorate the molecular defect in another subunit of TFIIH that causes a different, more severe repair syndrome: trichothiodystrophy. This commentary provides a broader historical, medical, and molecular context for the intricate genotype-phenotype relationship between compromised repair and its clinical consequences and discusses next steps for the advances reported.

Authors

Arjan F. Theil, Jan H.J. Hoeijmakers

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Figure 1

NER-associated disorders, TFIIH function, and a potential intervention for TTD-A.

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NER-associated disorders, TFIIH function, and a potential intervention f...
(A) Classification of XP, CS, and TTD in relation to functional defects in TFIIH. The primary clinical classifications overlap (XP/TTD, TTD/CS, XP/CS) based on which functions are affected. (* denotes that combined TTD/CS phenotype may best capture the clinical spectrum, rather than solely TTD). In TTD, TFIIH stability is affected, causing exhaustion of TFIIH, and, hence, of gene expression prior to completion of terminal differentiation. NER-disease–associated TFIIH subunits are indicated in dark gray (XPB, XPD) and orange (p8, defective in TTD-A cells), while purple highlights p52, which the related studies have associated with the NER-disease XP-J (9,10). (B) The stability and functions of the TFIIH complex critically depend on the p52–p8 interaction, where p8 is thought to remodel p52 homodimer to enable proper TFIIH assembly. In normal cells (leftmost column), WT p8 forms a stable heterodimer with the C-terminal domain of p52, enabling assembly with other TFIIH subunits, generating a fully functional TFIIH complex to carry out transcription, GG-NER, and TC-NER. In XP-J cells (second column), a mutation in GTF2H4 produces a C-terminally truncated p52 protein (p52ΔC), lacking the domain for p52 homo- or p52–p8 heterodimerization. p52ΔC remains capable of interacting with TFIIH, leading to near-normal levels of a p8-deficient TFIIH complex with impaired GG- and TC-NER but unaffected transcriptional functions (9). In TTD-A cells (third column), a mutation leads to a partially functional p8 protein, resulting in unstable p52–p8 heterodimers that impair integration into TFIIH. The resulting p8- and p52-deficient TFIIH complex becomes unstable, leading to low TFIIH levels and impaired transcription, GG-NER, and TC-NER functions. Nakazawa et al. adopted a strategy to intervene in TTD-A cells using ASOs to modulate p52 splicing (rightmost column): treatment of TTD-A cells with ASOs induced a XP-J–like p52ΔC. p52ΔC lacks the domain for interaction with the TTD-A p8 mutant protein, but can directly interact with TFIIH, restoring near-normal TFIIH levels and normal transcription. Thus, expression of p52ΔC can convert the severe TTD-A phenotype into the milder XP-J phenotype (10). The effect on GG- and TC-NER functions requires follow-up investigation.