XPB and XPD helicases in TFIIH orchestrate DNA duplex opening and damage verification to coordinate repair with transcription and cell cycle via CAK kinase

Fuss, Jill O.; Tainer, John A.

doi:10.1016/j.dnarep.2011.04.028

Cited by 148 publications

(142 citation statements)

References 180 publications

(287 reference statements)

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“…DNA charge transport has been suggested to activate MAPK signaling. 56,57 MAPK activation was also suggested from transcriptome analysis of another NER mutant, ercc-1 39 , where we found a strong correlation between genes regulated by the PMK-1 p38 MAPK and the ercc-1 data set. Together, these results suggest that NER function is not lifespan-limiting in C. elegans partially due to an adaptive transcriptome reprogramming involving activation of p38 MAPK stress-response signaling.…”

Section: Does Accumulation Of Cyclopurines Cause the Reduced Lifespansupporting

confidence: 72%

Active transcriptomic and proteomic reprogramming in theC. elegansnucleotide excision repair mutant xpa-1

Kassahun

Nilsen

2013

Worm

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O xidative stress promotes human aging and contributes to common neurodegenerative diseases. Endogenous DNA damage induced by oxidative stress is believed to be an important promoter of neurodegenerative diseases. Although a large amount of evidence correlates a reduced DNA repair capacity with aging and neurodegenerative disease, there is little direct evidence of causality. Moreover, the contribution of oxidative DNA damage to the aging process is poorly understood. We have used the nematode Caenorhabditis elegans to study the contribution of oxidative DNA damage and repair to aging. C. elegans is particularly well suited to tackle this problem because it has a minimum complexity DNA repair system, which enables us to circumvent the important limitation presented by the extensive redundancy of DNA repair enzymes in mammals. Oxidative DNA Damage and Aging in C. elegansThe free radical theory of aging is an example of a hypothesis that, because it intuitively makes sense, is attractive both to scientists and to the general public. The theory has been enormously influential and has inspired scientists to test its implications ever since its first formulation by Denham Harman. 1 As such it is a good theory because it suggests many testable hypotheses. However, few experiments have provided direct support of the original theory. This has led to the formulation of many offshoots like the mitochondrial theory of aging and the stochastic damage accumulation theory of aging.One prediction that can be made from all of these theories is that oxidative damage to cellular macromolecules contributes to the progressive loss of function associated with aging. As DNA, unlike other cellular macromolecules, cannot be replaced in its entirety, it seems logical that maintenance of genomic stability would promote longevity and limit functional loss during aging.A role for passive and stochastic accumulation of oxidative DNA damage in aging is often dismissed by scientists outside the DNA repair field for three principal reasons; first, even though levels of reactive oxygen species (ROS) increase with age 2,3 and DNA repair capacity diminishes with age, 4 it has been difficult to unequivocally show that oxidative DNA damage accumulates with age. Also, since a plethora of different types of DNA lesions are induced by ROS, it is not entirely clear which types of lesions are more relevant to the aging phenotype. Second, there is no good correlation between mutation accumulation and aging. [5][6][7] Third, mutants that fail to repair oxidative DNA damage show normal lifespan. However, there are technical and biological factors that would explain these observations and further research is needed to determine whether and how oxidative DNA damage contributes to aging. Segmental Progeroid NER SyndromesIt is often overlooked that DNA damage may not only be mutagenic, but also

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Section: Does Accumulation Of Cyclopurines Cause the Reduced Lifespansupporting

confidence: 72%

Active transcriptomic and proteomic reprogramming in theC. elegansnucleotide excision repair mutant xpa-1

Kassahun

Nilsen

2013

Worm

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“…Mutations in the human XPD helicase gene (ERCC2) lead to the genetic disorders trichothiodystrophy (TTD), Cockayne syndrome (CS), and xeroderma pigmentosum (XP) (28)(29)(30)(31). There is now evidence that mutations specifically in the iron-sulfur cluster domain of XPD result in TFIIH instability, thus leading to TTD (28,30).…”

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confidence: 99%

“…XPD, an ATP-dependent 5′-3′ helicase from the NER pathway, is a major component of TFIIH, the transcriptional and repair machinery that unwinds damaged DNA for lesion repair in NER (28,29). Mutations in the human XPD helicase gene (ERCC2) lead to the genetic disorders trichothiodystrophy (TTD), Cockayne syndrome (CS), and xeroderma pigmentosum (XP) (28)(29)(30)(31).…”

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confidence: 99%

DNA charge transport as a first step in coordinating the detection of lesions by repair proteins

Sontz

Mui

Fuss

et al. 2012

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

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Damaged bases in DNA are known to lead to errors in replication and transcription, compromising the integrity of the genome. We have proposed a model where repair proteins containing redoxactive [4Fe-4S] clusters utilize DNA charge transport (CT) as a first step in finding lesions. In this model, the population of sites to search is reduced by a localization of protein in the vicinity of lesions. Here, we examine this model using single-molecule atomic force microscopy (AFM). XPD, a 5′-3′ helicase involved in nucleotide excision repair, contains a [4Fe-4S] cluster and exhibits a DNAbound redox potential that is physiologically relevant. In AFM studies, we observe the redistribution of XPD onto kilobase DNA strands containing a single base mismatch, which is not a specific substrate for XPD but, like a lesion, inhibits CT. We further provide evidence for DNA-mediated signaling between XPD and Endonuclease III (EndoIII), a base excision repair glycosylase that also contains a [4Fe-4S] cluster. When XPD and EndoIII are mixed together, they coordinate in relocalizing onto the mismatched strand. However, when a CT-deficient mutant of either repair protein is combined with the CT-proficient repair partner, no relocalization occurs. These data not only indicate a general link between the ability of a repair protein to carry out DNA CT and its ability to redistribute onto DNA strands near lesions but also provide evidence for coordinated DNA CT between different repair proteins in their search for damage in the genome.DNA electron transfer | iron-sulfur clusters | oxidative damage

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confidence: 99%

“…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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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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XPB and XPD helicases in TFIIH orchestrate DNA duplex opening and damage verification to coordinate repair with transcription and cell cycle via CAK kinase

Cited by 148 publications

References 180 publications

Active transcriptomic and proteomic reprogramming in theC. elegansnucleotide excision repair mutant xpa-1

Active transcriptomic and proteomic reprogramming in theC. elegansnucleotide excision repair mutant xpa-1

DNA charge transport as a first step in coordinating the detection of lesions by repair proteins

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

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