TFIIH: when transcription met DNA repair

Compe, Emmanuel; Egly, Jean‐Marc

doi:10.1038/nrm3350

Cited by 284 publications

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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).…”

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“…Notably, premalignant skin lesions and cutaneous tumors have never been reported in TTD. It was suggested that pathological features of XP are associated with mutations that mainly affect the DNA repair activity of TFIIH, whereas those typical of TTD also impair transcription (12,(17)(18)(19).To assess whether mutated TFIIH in TTD might alter the transcription of ECM-related genes (thus affecting the strength Significance Despite exhibiting different phenotypes, the UV-sensitive syndromes trichothiodystrophy (TTD) and xeroderma pigmentosum (XP) result from the same mutated genes encoding specific subunits of the DNA-repair/transcription factor TFIIH. The widely accepted notion is that XP cancer proneness results from mutations interfering with DNA repair, whereas TTD clinical hallmarks (namely, hair anomalies, physical and mental retardation, and premature aging) are because of transcriptional alterations.…”

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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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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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“…NER은 DNA 손상을 인식하는 방법에 따라 global genome repair (GGR)와 transcription-coupled repair (TCR)의 두 가지 경로로 나누어진 다. 이 두 경로는 DNA 손상을 인식하는 초기 단계에서는 일련 의 서로 다른 단백질들이 관여하지만, 그 이후에는 DNA 손상확 인, 이중나선 풀기, 손상된 가닥 자르기 등의 공통된 단계들을 거 친다 (Prakash and Prakash, 2000;Compe and Egly, 2012).…”

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“…TFIIH 복합체에는 helicase인 Rad25와 Rad3 (각각 인간 XPB와 XPD의 orthologue)가 포함되 어 있는데, 이들은 DNA 손상부위를 확인하고 여는 역할을 한 다. 그 다음으로 또 다른 손상된 DNA 결합단백질인 Rad14 (인 간 XPA의 orthologue)과 RPA 등이 결합하여 pre-incision 복합 체를 형성한다 (Mardiros et al, 2011;Compe and Egly, 2012).…”

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Characterization of Hrq1-Rad14 Interaction in Saccharomyces cerevisiae

민문희¹,

김민지²,

최유진³

et al. 2014

The Korean Journal of Microbiology

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Hrq1 is a novel member of RecQ helicase family, found in fungal genomes by bioinformatics analyses. It is most homologous to human RECQL4 and recent genetic and biochemical studies suggested that it may play roles in the maintenance of genome stability. In this study, we investigated yeast two-hybrid interactions between Hrq1 and the yeast genes homologous to the human genes that are known to interact with RECQL4. Among the 11 genes tested, Rad14, a nucleotide excision repair (NER) factor, was found to interact with Hrq1. In addition, pull-down assay with the purified proteins revealed direct protein-protein interaction between Hrq1 and Rad14. The yeast two-hybrid interaction was enhanced by the DNA damage induced by 4-nitroquinoline-1-oxide, which was dependent on the presence of Rad4, a key NER factor. These results suggest that Hrq1 may function in NER through interaction with Rad14.

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The Transcription/ DNA Repair Factor TFIIH

Radu

Poterszman

2013

Encyclopedia of Life Sciences

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Transcription factor IIH (TFIIH) is a eukaryotic multicomponent macromolecular assembly composed of 10 subunits including two deoxyribonucleic acid (DNA)‐dependent helicase activities of opposite polarities and a kinase . Mutations in the helicases xeroderma pigmentosum group D protein (XPD) and xeroderma pigmentosum group B protein (XPB) as well as in the p8/TTD‐A subunit of human TFIIH are associated with three dramatic genetic disorders: xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD). Initially recognised as a basal factor responsible for transcription initiation of protein coding genes and transition from initiation to elongation, TFIIH also plays a critical role in nucleotide excision repair via its DNA‐opening helicase activity at the site of a lesion. A subcomplex, harbouring its kinase activity, phosphorylates the carboxy‐terminal domain (CTD) of ribonucleic acid (RNA) polymerase II as well as a number of transcription regulators including nuclear hormone receptors. Key Concepts: TFIIH is a prime example of multienzyme multitasking macromolecular assembly. Recent data suggest that several components are found in nonTFIIH complexes and that the function of TFIIH is regulated by its subunit composition. The human transcription/DNA repair factor TFIIH is a multi‐subunit complex composed two functional and structural entities: core‐TFIIH consists of XPB, p62, p52, p44, p34 and p8, whereas the CDK‐activating kinase (CAK) subcomplex contains cyclin‐dependent kinase 7 (CDK7), cyclin H and MAT1. XPD bridges the core‐TFIIH to the CDK activating kinase (CAK) complex, which also exists as a free complex with a distinct function. Although identified as a basal factor responsible for transcription initiation, TFIIH also plays a critical role in nucleotide excision repair and is implicated in the control of cell cycle progression. Key insights into TFIIH result from investigations centred on the analysis of mutations identified in XP, CS and TTD patients. Most mutations identified in patients reside within the noncatalytic regions of the helicases and do not affect the enzymatic activity of TFIIH per se but rather disturb the interactions of the catalytic subunits with their regulatory partners, impairing transcription and DNA repair.

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TFIIH: when transcription met DNA repair

Cited by 284 publications

References 201 publications

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

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

Characterization of Hrq1-Rad14 Interaction in Saccharomyces cerevisiae

The Transcription/ DNA Repair Factor TFIIH

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