Clinical implications of the basic defects in Cockayne syndrome and xeroderma pigmentosum and the DNA lesions responsible for cancer, neurodegeneration and aging

Cleaver, James E.; Revet, Ingrid

doi:10.1016/j.mad.2008.01.005

Cited by 24 publications

(18 citation statements)

References 82 publications

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“…1C) (Tables 1 and 2). Interestingly, these differences in transcriptional dysregulation parallel the clinical severity of the XP-D/CS vs. XP-D cases, thus underscoring their importance (Table 1) (13,17,33,34).…”

Section: Xp-d/cs Cells Display Global Transcriptional Dysregulation Amentioning

confidence: 90%

Sirt1 suppresses RNA synthesis after UV irradiation in combined xeroderma pigmentosum group D/Cockayne syndrome (XP-D/CS) cells

Vélez-Cruz

Zadorin

Coin

et al. 2012

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

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Specific mutations in the XPD subunit of transcription factor IIH result in combined xeroderma pigmentosum (XP)/Cockayne syndrome (CS), a severe DNA repair disorder characterized at the cellular level by a transcriptional arrest following UV irradiation. This transcriptional arrest has always been thought to be the result of faulty transcription-coupled repair. In the present study, we showed that, following UV irradiation, XP-D/CS cells displayed a gross transcriptional dysregulation compared with "pure" XP-D cells or WT cells. Furthermore, global RNA-sequencing analysis showed that XP-D/CS cells repressed the majority of genes after UV, whereas pure XP-D cells did not. By using housekeeping genes as a model, we demonstrated that XP-D/CS cells were unable to reassemble these gene promoters and thus to restart transcription after UV irradiation. Furthermore, we found that the repression of these promoters in XP-D/CS cells was not a simple consequence of deficient repair but rather an active heterochromatinization process mediated by the histone deacetylase Sirt1. Indeed, RNA-sequencing analysis showed that inhibition of and/or silencing of Sirt1 changed the chromatin environment at these promoters and restored the transcription of a large portion of the repressed genes in XP-D/CS cells after UV irradiation. Our work demonstrates that a significant part of the transcriptional arrest displayed by XP-D/CS cells arises as a result of an active repression process and not simply as a result of a DNA repair deficiency. This dysregulation of Sirt1 function that results in transcriptional repression may be the cause of various severe clinical features in patients with XP-D/ CS that cannot be explained by a DNA repair defect.nucleotide excision repair | sirtuins | aging | progeria

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Section: Xp-d/cs Cells Display Global Transcriptional Dysregulation Amentioning

confidence: 90%

Sirt1 suppresses RNA synthesis after UV irradiation in combined xeroderma pigmentosum group D/Cockayne syndrome (XP-D/CS) cells

Vélez-Cruz

Zadorin

Coin

et al. 2012

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

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“…Early diagnosis and immediate implementation of rigorous sun-protection measures may prolong the lives of persons with XP. About two thirds of unmanaged subjects die before the age of 20 years [1,4], but in climates with intense sunlight exposure, children with XP who do not implement sun-protection measures and have limited access to modern medical care, have a life expectancy of about 10 years [6]. Persons with XP must avoid exposure to any sources of UV light including sunlight, fluorescent, halogen and mercury-vapour lights [5], and must wear protective clothing and UV-absorbing eye glasses, and must use high protection factor sunscreens [1].…”

Section: Discussionmentioning

confidence: 99%

Xeroderma Pigmentosum: A Bane in developing country – Brief report

Yadalla¹,

Juwariya²

2014

Our Dermatol Online

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IntroductionXeroderma pigmentosum is a rare, genetically heterogeneous, autosomal recessive disorder characterized by photosensitivity, cutaneous pigmentary changes, premature skin ageing, and the development of various cutaneous and internal malignancies at an early age. The basic defect underlying the clinical manifestations is a nucleotide excision repair (NER) defect leading to a defective repair of DNA damaged by ultra violet (UV) radiation [1]. XP is characterized by clinical and cellular hypersensitivity to UV radiation manifesting as intolerance of skin and eyes to light. The skin lesions are comprised of freckles on limbs and face with a dry skin covered with a mixture of mottled, hypopigmented and hyperpigmented, atrophic rounded and oval macules, giving the entire skin a checkered appearance associated with a generalized actinic keratoses, manifesting on black skin as palpable, rough, blackish spots covered with adherent scales [2,4]. These skin lesions cover both the sun exposed and covered areas. The skin later develops cutaneous malignancies. Ocular changes include photophobia, ocular pigmentary changes, conjunctivitis, corneal keratitis, ulcers, blindness, and malignancies. The diagnosis of XP can be established with studies performed in specialized laboratories. These studies include cellular hypersensitivity to UV radiation and chromosomal breakage studies, complementation

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“…These discoveries have driven the study of DNA repair, leading to the elucidation of multiple DNA repair pathways. Analysis of rare or familial cancer predisposition and/or aging syndromes has resulted in identification of genes responsible for the following syndromes: xeroderma pigmentosum, trichothiodystrophy, Cockayne syndrome, severe combined immunodeficiency, Werner syndrome, ataxia telangiectasia, Nijmegen breakage syndrome, Bloom syndrome, Rothmund-Thomson syndrome, breast cancer susceptibility, hereditary non-polyposis colorectal cancer (HNPCC), and Fanconi anemia (reviewed in [1][2][3]). Many of these syndromes also display phenotypes distinct from cancer and aging.…”

Section: Introductionmentioning

confidence: 99%

Haploinsufficiency in mouse models of DNA repair deficiency: modifiers of penetrance

Cabelof

2011

Cell. Mol. Life Sci.

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Mouse models of DNA repair deficiency are useful tools for determining susceptibility to disease. Cancer predisposition and premature aging are commonly impacted by deficiencies in DNA repair, presumably as a function of reduced genomic fitness. In this review, a comprehensive analysis of all DNA repair mutant mouse models has been completed in order to assess the importance of haploinsufficiency for these genes. This analysis brings to light a clear role for haploinsufficiency in disease predisposition. Unfortunately, much of the data on heterozygous models are buried or underinvestigated. In light of a better understanding that the role of DNA repair haploinsufficiency may play in penetrance of other oncogenic or disease causing factors, it may be in the interest of human health and disease prevention to further investigate the phenotypes in many of these mouse models.

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Clinical implications of the basic defects in Cockayne syndrome and xeroderma pigmentosum and the DNA lesions responsible for cancer, neurodegeneration and aging

Cited by 24 publications

References 82 publications

Sirt1 suppresses RNA synthesis after UV irradiation in combined xeroderma pigmentosum group D/Cockayne syndrome (XP-D/CS) cells

Sirt1 suppresses RNA synthesis after UV irradiation in combined xeroderma pigmentosum group D/Cockayne syndrome (XP-D/CS) cells

Xeroderma Pigmentosum: A Bane in developing country – Brief report

Haploinsufficiency in mouse models of DNA repair deficiency: modifiers of penetrance

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