A Tiny Protein Plays A Big Role In DNA Repair

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A Tiny Protein Plays A Big Role In DNA Repair

http://www.medicalnewstoday.com/medicalnews.php?newsid=43043

Two of DNA's worst enemies, ultraviolet light and chemical

carcinogens, can wreak havoc on the molecule by mutating individual

nucleotides or changing its physical structure. In most cases,

genomic integrity is restored by specialized suites of proteins

dedicated to repairing specific types of injuries. One mending

mechanism, called nucleotide excision repair (NER), recruits and

coordinates the services of roughly 25 proteins to recognize and

remove structure-impairing lesions, including those induced by

ultraviolet light. At the center of this effort is the ten-subunit

transcription/repair factor IIH (TFIIH) complex. As its name

suggests, in addition to its role in DNA repair, TFIIH also regulates

transcription.

In a new study published in this month's PLoS Biology, Giuseppina

Giglia-Mari, Jan Hoeijmakers, 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.