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Human Molecular Genetics, 2009, Vol. 18, Review Issue 2
doi:10.1093/hmg/ddp390
R224–R230
Trichothiodystrophy view from the molecular basis
of DNA repair/transcription factor TFIIH
Satoru Hashimoto and Jean Marc Egly
Department of Functional Genomics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/
ULP, BP 16367404 Illkirch Cedex, CU Strasbourg, France
Received July 28, 2009; Revised and Accepted August 13, 2009
Trichothiodystrophy (TTD) is a rare autosomal recessive disorder characterized by brittle hair and also
associated with various systemic symptoms. Approximately half of TTD patients exhibit photosensitivity,
resulting from the defect in the nucleotide excision repair. Photosensitive TTD is due to mutations in three
genes encoding XPB, XPD and p8/TTDA subunits of the DNA repair/transcription factor TFIIH. Mutations in
these subunits disturb either the catalytic and/or the regulatory activity of the two XPB, XPD helicase/
ATPases and consequently are defective in both, DNA repair and transcription. Moreover, mutations in any
of these three TFIIH subunits also disturb the overall architecture of the TFIIH complex and its ability to transactivate certain nuclear receptor-responsive genes, explaining in part, some of the TTD phenotypes.
INTRODUCTION
DNA can undergo various modifications, including strand
break, base damage, helix distortion and strand cross-link
from endogenous (reactive oxidative species) and exogenous
sources (UV radiation). To maintain genome integrity and to
avoid harmful effects of DNA damage, cells possess several
DNA repair pathways that can be differentiated biochemically
and genetically. If not repaired, the damaged DNA can lead to
a range of human disorders that exhibit developmental defects,
neurological abnormalities, photosensitivity, cancer and accelerate the aging process (1).
Nucleotide excision repair (NER) is one of the most important DNA repair system and is responsible for removing
several kinds of DNA lesions, particularly those induced by
anti-tumorigenic drugs and UV irradiation, such as cyclobutane pyrimidine dimmers (CPD) and pyrimidine (6-4) pyrimidone photoproduct, which distort the DNA helix. Defects in
NER results in rare autosomal recessive diseases, known as
xeroderma pigmentosum (XP), Cockayne syndrome (CS)
and trichothiodystrophy (TTD) (2). Mutations in eleven
genes have been associated with these diseases (3,4). The products of these genes participate in NER, and three of these
eleven genes (XPB, XPD and p8/TTDA) are part of the basal
transcription/repair factor TFIIH. Intensive work has been performed to understand why mutations in TFIIH and particularly
in the XPD gene cause XP, CS and TTD (5). Here, we will
consider the molecular functions of TFIIH and examine how
a defect in one of them, may lead to the pathology of TTD.
CLINICAL FEATURES
TTD is a rare autosomal recessive disorder characterized by
sulfur-deficient brittle hair and neuroectodermal symptoms
(6). Clinical features of TTD are highly variable in expression,
including Photosensitivity, Icthyosis, Brittle hair and nails,
Intellectual impairment, Decreased fertility and Short stature
(7,8). The acronyms, PIBIDS, IBIDS and BIDS represent the
initials of these words. Light microscopy test of hair shaft
reveals trichoschisis; there is a cleaving, breaking, irregular
and flattening hair surface like a trichorrhexis nodosa. Polarizing microscopy shows the typical appearance of alternating
light and dark bands, giving a ‘tiger tail’ pattern. There is
no correlation between the extent of hair abnormalities and
the severity of the rest of the clinical phenotype. However,
amino acid analysis that quantifies sulfur (specifically
cysteine), inversely correlates with the percentage of hairs
showing one or more abnormalities and remains the definitive
diagnostic test for TTD (7). In addition, the increased proportion of unstable disulfide conformers contributes to the
reduced hair robustness (9). The sulfur-deficient brittle hair
phenotype is not seen in either XP or CS patients (Table 1).
Clinical manifestations of more than 100 TTD patients from
20 countries all over the world, reported in the last 40 years,
To whom correspondence should be addressed. Tel: þ33 388653447; Fax: þ33 388653201; Email: [email protected]
# The Author 2009. Published by Oxford University Press. All rights reserved.
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Human Molecular Genetics, 2009, Vol. 18, Review Issue 2
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Table 1. Clinical features of three NER defective disorders, XP, CS and TTD
Clinical features
XP
CS
TTD
Photosensitivity
Skin cancer
Brittle hair
Developmental delay
Neurological defects
þ
þ
2
2
+
þ
2
2
þ
þ
+
2
þ
þ
þ
were statistically reviewed (10). The incidence for TTD was
estimated at one per million in Western Europe. Only one
TTD patient was found in Japan (11, personal communication). However, in Japan, the incidence for XP is 1 per
20 000 – 100 000 (12,13). The number of deaths at a young
age of TTD patients is 20-fold higher compared with the
US general population (10).
Cellular studies revealed that the photosensitive form of
TTD is caused by the defective NER, also observed in XP
and CS; however, non-photosensitive TTD display a normal
NER capacity (14). Despite the fact that photosensitive TTD
patients have a defect in the same gene as some XP patients
characterized by photo-induced skin cancers, the TTD patients
do not have an increased incidence of skin cancers (15)
(Table 1). Neuroimaging examination revealed that the most
common feature of TTD was hypomyelination, also found in
CS patients. However, contrary to what occurs in CS, neurological abnormalities in TTD patients seemed to be caused
by developmental defect (dysmyelination) rather than loss of
myelin (demyelination). Progressive neurological degeneration was not reported in TTD patients (16).
GENETICS
Genetic complementation experiments (17) revealed that
photosensitive TTD patients only result from mutations in
XPD, XPB and p8/TTDA, three of the ten subunits of TFIIH.
Moreover, in cells derived from TTD patients, the cellular
concentration of TFIIH is significantly reduced (18,19).
However, neither the extent of the DNA repair defect nor
the degree of reduction in the level of TFIIH correlate with
the severity of the clinical phenotype. A reduced (and even
more significant reduction) level of TFIIH was also found in
cells from some XPD patients.
Most of photosensitive TTD cases are mutated in the XPD
gene, and the mutations are mostly located either at the
R112 loop or at the C-terminal end of the protein (20 – 22)
(Fig. 1). It should be mentioned that in a certain number of
cases, different phenotypes were described for the same
mutation, but the severity of clinical phenotype apparently
correlates with the nature of the mutation located on the
second allele, thus suggesting that both alleles might contribute to the TTD phenotype (23, unpublished data).
Epidemiological studies revealed that XPD, p.H201Y,
p.D312N and p.K751Q polymorphisms, might correlate with
either lung, colorectal, bladder or breast cancer but not with
TTD-like symptoms. In vitro studies further demonstrated
that recombinant TFIIH containing XPD polymorphism have
normal DNA repair and basal transcription in vitro (24).
Figure 1. Functional domain and TTD mutation sites on p8/TTDA, XPB and
XPD gene: XPB and XPD have two helicase domain HD1 (motif I, Ia, II and
III: orange) and HD2 (motif IV, V and VI: yellow). There are unique domain
exist; RED and thumb in XPB, and 4FeS and Arch in XPD, respectively. XPB
has a damage recognition domain (DRD: green). Reported mutation sites are
labeled.
This result indicates that for XPD, the single polymorphisms
seem to be benign. It is also likely that combination of
several polymorphisms, including that of XPD, might contribute to the ‘cancer’ phenotype.
Three mutations were found in XPB (XP mutation database:
http://xpmutations.org); only the T119P mutation results in
TTD. The tenth subunit of TFIIH, p8/TTDA, was recently
identified as a responsible gene for the third group of photosensitive TTD-A (25). Patient cells with either p8/TTDA
L21P, R56stop or T to C transition at start codon mutations
are deficient in the p8/TTDA protein.
C7orf11 (TTDN1) was identified as the first disease gene for
the remaining non-photosensitive form of TTD (26).
Mutations were found in only six of the 44 unrelated nonphotosensitive TTD patients (27). The TTDN1 patients are
not defective in NER and the steady state level of TFIIH is
normal. The severity of the clinical features does not correlate
with the mutation map in TTDN1, suggesting that nonphotosensitive TTD might be multi-factorial disease. Other
factors besides TTDN1 mutations might influence the phenotype of this disorder. Indeed, it was shown that TTDN1
interacts with polo-like kinase1 through the phosphorylation
by Cdk1 and plays a role in regulating mitosis and
cytokinesis (28).
TFIIH IN NER
NER is a multi-step process, which proceeds via at least two
alternative pathways. One is transcription-coupled DNA
repair (TCR), which removes lesions only in the actively transcribed DNA strand, and the other is global genome repair
(GGR), which removes lesions in any sequence of the
genome (29). In eukaryotic cells, the process requires
more than 30 proteins that sequentially target the damaged
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Human Molecular Genetics, 2009, Vol. 18, Review Issue 2
Figure 2. Functional and disease states of TFIIH complex. (A) TFIIH consists of two modules, core (green: XPB, XPD, red: p62, p52, p44, p34 and p8) and CAK
(yellow: cdk7, cyclinH and Mat1). CAK is dispensable for NER, although entire TFIIH is necessary for transcription. (B– E) Mutations in XPB, XPD, p8/TTDA
and Dmp52 Drosophila homolog of p52 lead to a instability of TFIIH resulting in TTD phenotype.
DNA: recognition of DNA damage, opening of the DNA
around the lesions, single-strand incisions and excision of
the lesion-containing DNA fragment, and gap filling DNA
synthesis and ligation (30,31). Human TFIIH consists of a
core of seven subunits: XPB, XPD, p62, p52, p44, p34 and
p8/TTDA. This core forms a ring-shaped structure, that is
associated to a module of cdk-activating kinase (CAK) composed of Cdk7, cyclin H and MAT1 (32). Once recruited to
the site of DNA damage, either by XPC/HR23B (in GGR)
or by the stalled RNA polymerase II (in TCR), TFIIH opens
the DNA around the lesion and promotes the subsequent
incision and excision, in both TCR and GGR, by recruiting
the XPG and XPF endonucleases (33,34). To make the DNA
‘bubble’, the TFIIH core module drives its two helicaseproteins with ATP hydrolysis, whereas CAK is released
from the core upon arrival of XPA and the other NER
factors (35). Although the CAK kinase activity is critical in
the basal transcription through the phosphorylation of Cterminal domain of the largest subunit of RNA polymerase
II and many nuclear receptors (36,37), it is dispensable for
the NER (Fig. 2A).
XPB
It has been predicted that DNA opening around the lesion
could be driven through the helicase activity of XPB (38).
A recent study has shown that the XPB helicase activity is
not crucial in NER (39). It seems, however, that its ATPase
activity rather than its helicase activity, in combination with
the helicase activity of XPD, is needed to remove the DNA
lesions. In addition to its seven helicase motifs, one of them
being the ATP binding site, XPB possess two additional
‘ATPase’ motifs: the well-conserved R-E-D residue loop
motif (at amino acids 472– 474) and the positively charged
thumb (ThM) region (at amino acids 514 – 537) (40) (Fig. 1).
These motifs are specifically involved in the regulation of
the DNA-dependant ATPase activity of XPB and help to
stabilize the binding of TFIIH to the damaged DNA (41), to
allow the recruitment of other NER factors. The XPB/T119P
mutation might disturb the TFIIH architecture, even though
located out of any helicase/ATPase motifs (Fig. 2B).
Another subunit of TFIIH, p52, interacts with XPB and
stimulates its ATPase activity (42). Mutation in the Drosophila homolog of p52, Dmp52, destabilizes its interaction
with XPB and results in a fly with UV sensitivity, cancer
prone, brittle-bristle with cuticular-deformation and developmental defects. Some of these phenotypes displayed by this
mutant fly were also observed in human TTD and XP (43)
(Fig. 2C). Although it was found that mutation in p52 may
abolish the physical and functional interaction between XPB
and other factors in transcription or DNA repair, human
with mutations in the p52 gene have never been identified.
XPD
In addition to XPB, TFIIH contains another DNA helicase
subunit, XPD, which is dispensable for transcription initiation
but plays a critical role in opening the DNA around lesions
during NER (44 – 46). Recent structural studies of XPD
revealed a four-domain structure consisting of two canonical
helicase domains (HD1: helicase motif I, Ia, II and III, and
HD2: helicase motif IV, V and VI), the iron-sulfur cluster
binding (4FeS) and Arch domains (47 –49) (Fig. 1).
However, there is no relationship between the structural placement of the XPD mutations and the TTD phenotype. It is likely
that the TTD mutations dispersed throughout all four domains
might disturb the network of interactions between the various
TFIIH subunits affecting the integrity of the complex
(Fig. 2D).
Despite it is generally believed that the elevated incidence
of cancer in patients with XP is a consequence of defective
NER, one wonder why patients with photosensitive TTD are
not cancer prone? Some answers might come from immunocytochemistry studies (50). It was observed that after UV
irradiation, NER factors assemble at the damage site rapidly
and are redistributed all over the nucleus, after completing
the repair of most of the damaged DNA. XPC, the
damage-recognition protein, localizes to damage sites rapidly
Human Molecular Genetics, 2009, Vol. 18, Review Issue 2
in both XP and TTD cells (as well as in wild-type cells).
However, in XP cells, XPC remains at damage site for more
than 24 h, whereas in TTD cells XPC is redistributed 3 h
after UV irradiation. Moreover, XP cells show a delay in
recruiting TFIIH and this complex remains on the damage
site over 24 h post-UV irradiation, whereas in TTD cells,
TFIIH is hardly recruited to the DNA damage, (especially to
CPD damage site) (51,52). These results partially support
the hypothesis that although XP and TTD cells are both
deficient in NER, the absence of NER complexes in TTD, at
the damage site, may allow the trans-lesion synthesis or postreplication repair. In contrast, in XP cells, the persistence of
NER factors at unrepaired sites may prevent any replication
and/or transcription processes, resulting to genomic instability
and an increase of cancer development.
As observed in the partnership XPB/p52, XPD interacts
with p44, another subunit of TFIIH, and this association upregulates the helicase activity of XPD, but not its ATPase
activity (46). Most of the XPD mutations are located in its Cterminal part and thus weaken its interaction with the Nterminal of p44, explaining the NER defect in these patients.
Interestingly, p44 (as well as the p34 subunit) possesses a
RING finger domain, typical of E3 ubiquitin ligase enzymes
(53). Ssl1p, the budding yeast homolog of p44, exhibits an
E3 ubiquitin ligase activity likely implicated in transcription
(54). Although the role of p44 in regulating the helicase
activity of XPD, and thus NER, is well established, no patients
with mutations in the p44 gene have ever been identified (55).
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Table 2. Ten subunits of TFIIH complex
Subunit
Core
XPB
XPD
p62
p52
p44
p34
p8
CAK
cdk7
cyclinH
Mat1
Function
Helicase/ATPase
Helicase/ATPase
?
XPD regulation
XPB regulation
?
Core stability/ATPase regulation
Kinase
Kinase regulation
CAK stability
that TFIIH can undergo and how these modifications can
modulate the activity of the complex could potentially aid us
in the understanding of the molecular basis of the TTD phenotype. The ubiquitin proteasome degradation pathway seems to
be implicated in the regulation of DNA repair (62). This is not
so surprising given the fact that XPB was shown to interact
with SUG1, a subunit of 26S proteasome (63). Moreover, ubiquitination of MAT1 regulates CAK activity (64). Other posttranslational modification, such as the phosphorylation of
XPB, might regulate NER, by preventing the further incision
step by the XPF-ERCC1 endonuclease (65). Despite of
many studies, unclear function and modification of every subunits of TFIIH still exist (Table 2).
p8/TTDA
Mutations in p8/TTDA, the tenth and smallest subunit of the
TFIIH complex, only causes TTD (26,56). p8/TTDA stimulates the ATPase activity of XPB in vitro through a direct
interaction with p52, which upregulates the activity of XPB
(57). The intricate network of interactions between these
three subunits was also demonstrated by genetic complementation experiments. Indeed, overexpression of p8/TTDA is
able to re-establish normal levels of TFIIH not only in the
TTD-A cells but also in TTD cells bearing mutations in
XPD and in Drosophila cells bearing a mutation in Dmp52,
the homolog of the human p52. These observations underline
the role of p8 as a stabilizer of TFIIH (58). Two distinct
kinetic pools of p8/TTDA exist: one is the form bound to
TFIIH and alternatively p8/TTDA exist as a free module
that shuttles between the cytoplasm and nucleus (59). Solution
structure study revealed that this latter form might exist as a
homodimer (60). After induction of DNA damage, the equilibrium between these two pools dramatically shifts towards a
more stable form within the TFIIH complex. Structural
studies revealed that the p8/TTDA L21P mutation possibly
disrupt its conformation. Furthermore, the R56stop mutation
weakens the interaction between p8/TTD-A and p52, and as
a consequence, the stability of TFIIH (61) (Fig. 2E).
Despite all the work done to dissect the functions of each
one of the TFIIH subunits, there is still a lot of work to be
done (Table 2). Similarly, there are still many potential
ways of modifying the function of this complex. Posttranslational modifications of proteins are central to most
aspects of cellular life and to investigate the modifications
TRANSCRIPTION SYNDROME
Defects in DNA repair cause not only TTD but also many disorders, such as XP, CS, Bloom syndrome, Werner syndrome,
Nijmegen breakage syndrome and Ataxia-telangiectasia
among others. Moreover, defective DNA repair has been
linked to neurological disorders (66). It must be noted that
NER activity is strongly attenuated in terminally differentiated
neurons (67). The fact that we observe neurological phenotypes (neurodegeneration) in a classical model of defective
DNA repair could suggest that the accumulation of DNA
damage causes neuronal death. However, UV penetrates
deep into the dermis of the skin but never into the central
nervous system (68). Moreover, it seems that the TTD patients
suffer much more from developmental defect, e.g. dysmyelination, rather than from neurodegeneration (69), suggesting
that the TTD phenotype arises from transcriptional deficiency.
Several studies show that NER factors are associated with
transcription of protein coding genes. TFIIH bearing mutations
in XPD, as found within TTD patients, but not XP patients,
exhibits a deficiency of basal transcription in vitro (45).
However, gene-expression profiling on microarrays of TTD
and XP fibroblasts showed no significant differences (70).
As the symptoms of TTD appear to be mainly caused by
developmental defects, it is possible that significant differences in transcription occur in differentiating cells and specific
tissues. A recent study in TTD mouse model highlights the
importance of the co-activator function of TFIIH in the pathogenesis of TTD (71). TTD/Xpd (R722W) mutant mice, carrying a mutation found in a human TTD patient, showed the
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similar phenotype to those of TTD individuals, such as motor
impairments associated with microcephaly and hypomyelination. It was suggested that such defects were due to a deregulation of thyroid hormone target genes in the central nervous
system. Indeed, TFIIH containing the R722W mutation
failed to properly stabilize the thyroid hormone receptor
(TR) to its binding site, resulting in a defect in the TR transactivation (72). Other mutations within XPD weakens the
anchoring of the CAK to the core of TFIIH and consequently
its capacity to phosphorylate PPARs, RARa and/or VDR partners (37,72– 75), which is required for efficient expression of
the hormone-responsive genes.
It is well accepted that the onset of photosensitivity associates with the defects of NER. However, the rest of the pathophysiological symptoms of TTD patients are rather
complicated. Currently, except for the TFIIH mutations and
their link to deficient NER, and TTDN1 gene responsible for
non-photosensitive TTD that regulates the mitosis and cytokinesis, no other mechanisms are linked to the TTD phenotype. Further studies of the cells from both photosensitive
and non-photosensitive TTD may provide a clue to pathophysiology of TTD and possibly unveil a new function of the versatile TFIIH complex.
ACKNOWLEDGEMENT
We are grateful to Renier Vélez-Cruz for critical reading of
the manuscript. S.H. is a recipient of INSERM MD young
investigator fellowship.
Conflict of Interest statement. None declared.
FUNDING
This study was supported by funds from an ERC
Advanced-Scientist Grant (to J.M.E.), Agence Nationale de
la Recherche (ANR-No 06-BLAN-0141-01 and ANR-No
08-MIEN-02203) and La Ligue contre la Cancer.
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