In a new study published in this month's PLoS Biology, Giuseppina Giglia-Mari, Jan Hoeijmakers, Catherine Miquel, Wim Vermeulen, and colleagues present their study investigating the contribution of trichothiodystrophy group A (TTDA) in DNA repair and transcription. TTDA is one of three TFIIH genes--XPB, XPD, and TTDA-- that have been implicated in the photosensitive form of a rare inherited premature aging syndrome called trichothiodystrophy (TTD), which is characterized by brittle hair and nails, scaly skin, and neurological degeneration.
To study the role of the TTDA subunit in the TFIIH complex's functions, the researchers tagged TTDA and the XPD subunit with green fluorescent protein (GFP) to monitor and compare their movement and behavior using high-resolution confocal microscopy. Both TTDA-GFP and XPD-GFP could stably incorporate into TFIIH and function in DNA repair; TTDA-GFP and XPD-GFP were observed in the cytoplasm and nucleus, in contrast to the XPB subunit, which is known to localize only in the nucleus. To determine if TTDA and XPD assemble with TFIIH in the cytoplasm, the researchers used a customized version of a motility-monitoring technique called fluorescence recovery after photobleaching (FRAP). They observed that TTDA dynamically associates with TFIIH, and that TTDA becomes stably incorporated only while the complex is engaged in NER (not while it is engaged in transcription).
Giglia-Mari et al. propose that once TTDA nestles into place after the core TFIIH complex attaches to a lesion, it triggers a conformational change that recruits the other subunits required for repair. TTDA may also help TFIIH fold properly, preventing it from being degraded and allowing it to accumulate to the levels necessary for NER function. These observations may explain why people who can't produce TTDA experience such debilitating symptoms.
Citation: Giglia-Mari G, Miquel C, Theil AF, Mari PO, Hoogstraten D, et al. (2006) Dynamic interaction of TTDA with TFIIH is stabilized by nucleotide excision repair in living cells. PLoS Biol 4(6): e156.
Erasmus Medical Center
Rotterdam, Netherlands 3000 DR
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