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2.
Photochem Photobiol ; 91(2): 254-64, 2015.
Article in English | MEDLINE | ID: mdl-25534312

ABSTRACT

Ultraviolet (UV) radiation from sunlight is a major etiologic factor for skin cancer, the most prevalent cancer in the United States, as well as premature skin aging. In particular, UVB radiation causes formation of specific DNA damage photoproducts between pyrimidine bases. These DNA damage photoproducts are repaired by a process called nucleotide excision repair, also known as UV-induced DNA repair. When left unrepaired, UVB-induced DNA damage leads to accumulation of mutations, predisposing people to carcinogenesis as well as to premature aging. Genetic loss of nucleotide excision repair leads to severe disorders, namely, xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS), which are associated with predisposition to skin carcinogenesis at a young age as well as developmental and neurological conditions. Regulation of nucleotide excision repair is an attractive avenue to preventing or reversing these detrimental consequences of impaired nucleotide excision repair. Here, we review recent studies on molecular mechanisms regulating nucleotide excision repair by extracellular cues and intracellular signaling pathways, with a special focus on the molecular regulation of individual repair factors.


Subject(s)
Aging/radiation effects , Cockayne Syndrome/metabolism , DNA Repair , Skin Neoplasms/metabolism , Trichothiodystrophy Syndromes/metabolism , Ultraviolet Rays/adverse effects , Xeroderma Pigmentosum/metabolism , Aging/genetics , Aging/metabolism , Carcinogenesis/genetics , Carcinogenesis/metabolism , Carcinogenesis/pathology , Cockayne Syndrome/etiology , Cockayne Syndrome/genetics , Cockayne Syndrome/pathology , DNA Repair Enzymes/genetics , DNA Repair Enzymes/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Gene Expression Regulation , Humans , RNA Polymerase II/genetics , RNA Polymerase II/metabolism , Signal Transduction , Skin Neoplasms/etiology , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Trichothiodystrophy Syndromes/etiology , Trichothiodystrophy Syndromes/genetics , Trichothiodystrophy Syndromes/pathology , Xeroderma Pigmentosum/etiology , Xeroderma Pigmentosum/genetics , Xeroderma Pigmentosum/pathology
4.
Ophthalmology ; 120(7): 1324-36, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23601806

ABSTRACT

OBJECTIVE: Xeroderma pigmentosum (XP) is a rare autosomal recessive disease caused by mutations in DNA repair genes. Clinical manifestations of XP include mild to extreme sensitivity to ultraviolet radiation resulting in inflammation and neoplasia in sun-exposed areas of the skin, mucous membranes, and ocular surfaces. This report describes the ocular manifestations of XP in patients systematically evaluated in the Clinical Center at the National Institutes of Health. DESIGN: Retrospective observational case series. PARTICIPANTS: Eighty-seven participants, aged 1.3 to 63.4 years, referred to the National Eye Institute (NEI) for examination from 1964 to 2011. Eighty-three patients had XP, 3 patients had XP/Cockayne syndrome complex, and 1 patient had XP/trichothiodystrophy complex. METHODS: Complete age- and developmental stage-appropriate ophthalmic examination. MAIN OUTCOME MEASURES: Visual acuity; eyelid, ocular surface, and lens pathology; tear film and tear production measures; and cytologic analysis of conjunctival surface swabs. RESULTS: Of the 87 patients, 91% had at least 1 ocular abnormality. The most common abnormalities were conjunctivitis (51%), corneal neovascularization (44%), dry eye (38%), corneal scarring (26%), ectropion (25%), blepharitis (23%), conjunctival melanosis (20%), and cataracts (14%). Thirteen percent of patients had some degree of visual axis impingement, and 5% of patients had no light perception in 1 or both eyes. Ocular surface cancer or a history of ocular surface cancer was present in 10% of patients. Patients with an acute sunburning skin phenotype were less likely to develop conjunctival melanosis and ectropion but more likely to develop neoplastic ocular surface lesions than nonburning patients. Some patients also showed signs of limbal stem cell deficiency. CONCLUSIONS: Our longitudinal study reports the ocular status of the largest group of patients with XP systematically examined at 1 facility over an extended period of time. Structural eyelid abnormalities, neoplasms of the ocular surface and eyelids, tear film and tear production abnormalities, ocular surface disease and inflammation, and corneal abnormalities were present in this population. Burning and nonburning patients with XP exhibit different rates of important ophthalmologic findings, including neoplasia. In addition, ophthalmic characteristics can help refine diagnoses in the case of XP complex phenotypes. DNA repair plays a major role in protection of the eye from sunlight-induced damage.


Subject(s)
DNA Repair/physiology , DNA/radiation effects , Eye Diseases/diagnosis , Radiation Injuries/diagnosis , Sunlight/adverse effects , Xeroderma Pigmentosum/diagnosis , Adolescent , Adult , Child , Child, Preschool , Cockayne Syndrome/diagnosis , Cockayne Syndrome/etiology , Cockayne Syndrome/prevention & control , Eye Diseases/etiology , Eye Diseases/prevention & control , Female , Follow-Up Studies , Humans , Infant , Male , Middle Aged , Radiation Injuries/etiology , Radiation Injuries/prevention & control , Retrospective Studies , Trichothiodystrophy Syndromes/diagnosis , Trichothiodystrophy Syndromes/etiology , Trichothiodystrophy Syndromes/prevention & control , Ultraviolet Rays/adverse effects , Visual Acuity/physiology , Xeroderma Pigmentosum/etiology , Xeroderma Pigmentosum/prevention & control , Young Adult
7.
J Investig Dermatol Symp Proc ; 14(1): 8-14, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19675546

ABSTRACT

Progeroid syndromes are a group of diseases characterized by signs of premature aging. These syndromes comprise diseases such as Werner syndrome, Bloom syndrome, Rothmund-Thomson syndrome, Hutchinson-Gilford syndrome, Fanconi anemia, and ataxia-telangiectasia, as well as xeroderma pigmentosum, trichothiodystrophy, and Cockayne syndrome. Clinical symptoms of premature aging are skin atrophy with loss of cutaneous elasticity, dysfunction of cutaneous appendices, degeneration of the central nervous system and an increased susceptibility for malignant tumors. Genetic defects in the repair of DNA damage can lead to progeroid syndromes, and it is becoming increasingly evident that direct DNA damage and indirect damage by highly reactive oxygen species play central roles in aging. The clinical signs of progeroid syndromes and the molecular aspects of UV (ultraviolet radiation)-induced oxidative stress in aging are discussed.Journal of Investigative Dermatology Symposium Proceedings (2009) 14, 8-14; doi:10.1038/jidsymp.2009.6.


Subject(s)
Cockayne Syndrome/etiology , DNA Damage , Ultraviolet Rays/adverse effects , Ataxia Telangiectasia/etiology , Bloom Syndrome/etiology , Cockayne Syndrome/genetics , Cockayne Syndrome/metabolism , DNA Repair , Fanconi Anemia/etiology , Female , Humans , Male , Models, Biological , Oxidative Stress/radiation effects , Progeria/etiology , Rothmund-Thomson Syndrome/etiology , Trichothiodystrophy Syndromes/etiology , Werner Syndrome/etiology , Xeroderma Pigmentosum/etiology
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