Basal Transcription Defect Discriminates between Xeroderma Pigmentosum and Trichothiodystrophy in XPD Patients

Dubaele, Sandy; Proietti-De-Santis, Luca; Bienstock, Rachelle J.; Keriel, Anne; Stefanini, Miria; Houten, Bennett Van; Egly, Jean‐Marc

doi:10.1016/s1097-2765(03)00182-5

Cited by 185 publications

(259 citation statements)

References 41 publications

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“…A mutant form of BACH1 (K52R) predicted to be enzymatically inactive (6) was generated in parallel. This conserved residue, when mutated in the XPD and ChlR1 helicases, rendered these proteins inactive (18)(19)(20). This same BACH1 mutation disrupted BRCA1-mediated DSBR (6).…”

Section: Resultsmentioning

confidence: 96%

The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations

Cantor

Drapkin²,

Zhang³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

219

247

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BACH1 is a nuclear protein that directly interacts with the highly conserved, C-terminal BRCT repeats of the tumor suppressor, BRCA1. Mutations within the BRCT repeats disrupt the interaction between BRCA1 and BACH1, lead to defects in DNA repair, and result in breast and ovarian cancer. BACH1 is necessary for efficient double-strand break repair in a manner that depends on its association with BRCA1. Moreover, some women with early-onset breast cancer and no abnormalities in either BRCA1 or BRCA2 carry germline BACH1 coding sequence changes, suggesting that abnormal BACH1 function contributes to tumor induction. Here, we show that BACH1 is both a DNA-dependent ATPase and a 5′-to-3′ DNA helicase. In two patients with early-onset breast cancer who carry distinct germline BACH1 coding sequence changes, the resulting proteins are defective in helicase activity, indicating that these sequence changes disrupt protein function. These results reinforce the notion that mutant BACH1 participates in breast cancer development

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Section: Resultsmentioning

confidence: 96%

The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations

Cantor

Drapkin²,

Zhang³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

219

247

View full text Add to dashboard Cite

show abstract

“…Mutations are spread out along the 761 amino-acid structure of XPD in both disorders 1,5,[8][9][10][11] The mutations may affect nucleotide-excision repair and/or transcription to different extents. 2,3 In addition, some mutations are found in both XP and TTD patients. As XPD is an essential part of the basal transcription factor TFIIH, complete absence of this protein is not compatible with life.…”

Section: Discussionmentioning

confidence: 99%

Effect of mutations in XPD(ERCC2) on pregnancy and prenatal development in mothers of patients with trichothiodystrophy or xeroderma pigmentosum

et al. 2012

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The XPD(ERCC2) gene encodes a DNA helicase involved in DNA repair and transcription. Patients with mutations in XPD may have different autosomal recessive phenotypes including trichothiodystrophy (TTD) or xeroderma pigmentosum (XP). TTD patients have sulfur-deficient, brittle hair, short stature and developmental delay. In contrast, XP patients have freckle-like pigmentation and a greatly increased risk of sun-induced skin cancers. Mothers of TTD patients have been reported to have a high frequency of pregnancy and neonatal complications. We performed a molecular epidemiological study of 15 mothers of 17 TTD patients and 13 mothers of 17 XP patients, all with XPD mutations. We found that 94% (16/17) of the TTD pregnancies had pre-term delivery, pre-eclampsia, hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, prematurity or low birth weight. None of the 17 XP pregnancies had these complications (Po0.001). As mutations in XPD may have differential effects on DNA repair and transcription, these observations should provide insights into the role of XPD in human pregnancy and fetal development. European Journal of Human Genetics (2012Genetics ( ) 20, 1308Genetics ( -1310 doi:10.1038/ejhg.2012; published online 23 May 2012Keywords: DNA repair; pre-eclampsia; transcription factor IIH INTRODUCTIONPatients with different mutations in the DNA repair/transcription helicase, XPD(ERCC2), may have markedly disparate autosomal recessive phenotypes, including trichothiodystrophy (TTD) or xeroderma pigmentosum (XP). 1-11 TTD patients have brittle hair, short stature, developmental delay and multisystem involvement without increased skin cancer risk. 12 In contrast, XP patients have sun sensitivity, freckle-like skin pigmentation, a 10 000-fold increase in skin cancer, and 25% have progressive neurologic degeneration. 12,13 At the National Institutes of Health (NIH), we have examined XP patients since 1971 and TTD patients since 2001 as part of a natural history protocol. 7,13 Our review of all English-language-published case reports of TTD patients found 112 TTD patients, of whom 55% had abnormal characteristics at birth and 28% had maternal pregnancy complications. 14 We then conducted two molecular epidemiological studies of pregnancy and neonatal abnormalities in mothers of TTD patients in our clinic. 15,16 We found that 81% of these pregnancies had complications, including 56% with preterm delivery, 30% with preeclampsia and 11% with hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. 16 The TTD patients had mutations in TTD-A(GTF2H5) or TTDN1(C7orf11) in addition to XPD and unknown genes. In contrast, our 1987 review of all Englishlanguage-published case reports of XP patients did not identify a large number of pregnancy abnormalities in 830 XP case reports. 17 These patients had mutations in at least 8 different genes involved in nucleotide excision repair and polymerase function. 7 In order to determine the influence of the XPD gene, we now have conducted a molecular epidemiological s...

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“…The genes responsible for the photosensitive form of TTD encode the XPB, XPD, and p8/TTDA subunits of the general transcription factor IIH (TFIIH). All of the mutations associated with TTD result in reduced cellular levels (8,9) and impaired functioning of TFIIH in NER and basal transcription (10)(11)(12). Furthermore, they may interfere with the role of TFIIH in transcription regulation (13)(14)(15)(16).…”

mentioning

confidence: 99%

TFIIH-dependent MMP-1 overexpression in trichothiodystrophy leads to extracellular matrix alterations in patient skin

Arseni

Lanzafame

Compe

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in the XPD subunit of the DNA repair/transcription factor TFIIH result in distinct clinical entities, including the cancerprone xeroderma pigmentosum (XP) and the multisystem disorder trichothiodystrophy (TTD), which share only cutaneous photosensitivity. Gene-expression profiles of primary dermal fibroblasts revealed overexpression of matrix metalloproteinase 1 (MMP-1), the gene encoding the metalloproteinase that degrades the interstitial collagens of the extracellular matrix (ECM), in TTD patients mutated in XPD compared with their healthy parents. The defect is observed in TTD and not in XP and is specific for fibroblasts, which are the main producers of dermal ECM. MMP-1 transcriptional up-regulation in TTD is caused by an erroneous signaling mediated by retinoic acid receptors on the MMP-1 promoter and leads to hypersecretion of active MMP-1 enzyme and degradation of collagen type I in the ECM of cell/tissue systems and TTD patient skin. In agreement with the well-known role of ECM in eliciting signaling events controlling cell behavior and tissue homeostasis, ECM alterations in TTD were shown to impact on the migration and wound-healing properties of patient dermal fibroblasts. The presence of a specific inhibitor of MMP activity was sufficient to restore normal cell migration, thus providing a potential approach for therapeutic strategies. This study highlights the relevance of ECM anomalies in TTD pathogenesis and in the phenotypic differences between TTD and XP.T he extracellular matrix (ECM) is a complex structural network that surrounds and supports cells within connective tissues. It generally includes three major types of macromolecules: fibrous proteins (collagens and elastic fibers), glycoproteins (such as fibronectins and laminins), and glycosaminoglycans/ proteoglycans. The type, amount and composition of the ECM give tissues their unique physical and biological properties (1). Notably, the ECM is not only a structural scaffold but also exhibits important functional roles in controlling key cellular events (e.g., adhesion, migration, proliferation, differentiation, and survival) involved in tissue homeostasis, development, inflammation, and tissue repair (2, 3). Thus, inherited or acquired structural alterations as well as metabolic disturbances of the ECM may cause cellular and tissue changes leading to the onset and progression of specific disorders, such as those affecting the connective tissues (osteogenesis imperfecta, Ehlers-Danlos syndrome, and Marfan's syndrome) or demanding ECM degradation (tumor invasion and metastasis) (4, 5). Recently, a reduced synthesis of the ECM component collagen type VI (COL6) was shown in confluent fibroblast cultures from patients with trichothiodystrophy [TTD; Online Mendelian Inheritance in Man (OMIM) #601675] (6), an autosomal recessive disorder characterized by symptoms affecting several tissues and organs (7). The most relevant features of TTD are hair abnormalities, ichthyotic skin, physical and mental retardation, neurodegeneration, and sign...

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Basal Transcription Defect Discriminates between Xeroderma Pigmentosum and Trichothiodystrophy in XPD Patients

Cited by 185 publications

References 41 publications

The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations

The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations

Effect of mutations in XPD(ERCC2) on pregnancy and prenatal development in mothers of patients with trichothiodystrophy or xeroderma pigmentosum

TFIIH-dependent MMP-1 overexpression in trichothiodystrophy leads to extracellular matrix alterations in patient skin

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