Ziani et al. reveal how a large DNA repair complex assembles incompletely on undamaged DNA.

The nucleotide excision repair pathway begins when the proteins XPC and hHR23b recognize damaged DNA and recruit the multisubunit transcription factor TFIIH. The transcription factor then recruits downstream repair factors such as XPA and the endonuclease XPF to form a preincision complex (PInC) that cuts out the damaged region of DNA. However, many components of the PInC, including XPC, have additional cellular functions that involve binding to undamaged stretches of DNA, suggesting that DNA lesions must somehow influence PInC assembly to promote the formation of active repair complexes.

Ziani et al. studied the PInC’s ability to assemble after tethering various components of the complex to undamaged chromatin. Immobilized XPC recruited several TFIIH subunits but failed to enlist the downstream factors XPA and XPF, indicating that damaged DNA is required to assemble a complete PInC. Immobilizing the TFIIH subunit XPB, on the other hand, bypassed the need for XPC or a DNA lesion, inducing the recruitment of XPA and XPF to undamaged chromatin.

The ability to recruit XPA and XPF depended on whether or not the small TFIIH subunit TTDA was incorporated into the PInC. Some patients with trichothiodystrophy produce a truncated version of TTDA that lacks 15 amino acids at its N terminus. Ziani et al. found that TTDA required these amino acids to bind XPA and recruit the repair protein to both damaged and undamaged DNA. Senior author Frédéric Coin now wants to investigate how other mutations in TTDA affect the protein’s function in nucleotide excision repair.

, et al
J. Cell Biol
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Author notes

Text by Ben Short