RESUMO
Cockayne syndrome (CS) is a genetic disorder characterized by developmental abnormalities and photodermatosis resulting from the lack of transcription-coupled nucleotide excision repair, which is responsible for the removal of photodamage from actively transcribed genes. To date, all identified causative mutations for CS have been in the two known CS-associated genes, ERCC8 (CSA) and ERCC6 (CSB). For the rare combined xeroderma pigmentosum (XP) and CS phenotype, all identified mutations are in three of the XP-associated genes, ERCC3 (XPB), ERCC2 (XPD), and ERCC5 (XPG). In a previous report, we identified several CS cases who did not have mutations in any of these genes. In this paper, we describe three CS individuals deficient in ERCC1 or ERCC4 (XPF). Remarkably, one of these individuals with XP complementation group F (XP-F) had clinical features of three different DNA-repair disorders--CS, XP, and Fanconi anemia (FA). Our results, together with those from Bogliolo et al., who describe XPF alterations resulting in FA alone, indicate a multifunctional role for XPF.
Assuntos
Síndrome de Cockayne/genética , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Anemia de Fanconi/genética , Predisposição Genética para Doença/genética , Fenótipo , Xeroderma Pigmentoso/genética , Sequência de Aminoácidos , Sequência de Bases , Síndrome de Cockayne/enzimologia , Síndrome de Cockayne/patologia , Primers do DNA/genética , Anemia de Fanconi/enzimologia , Anemia de Fanconi/patologia , Evolução Fatal , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Análise de Sequência de DNA , Xeroderma Pigmentoso/enzimologia , Xeroderma Pigmentoso/patologiaRESUMO
We have prospectively followed 16 Finnish xeroderma pigmentosum (XP) patients for up to 23 years. Seven patients were assigned by complementation analysis to the group XP-A, two patients to the XP-C group and one patient to the XP-G group. Six of the seven XP-A patients had the identical mutation (Arg228Ter) and the seventh patient had a different mutation (G283A). Further patients were assigned to complementation groups on the basis of their consanguinity to an XP patient with a known complementation group. The first sign of the disease in all the cases was severe sunburn with minimal sun exposure in early infancy. However, at the time the diagnosis was made in only two cases. The XP-A patients developed neurological and cognitive dysfunction in childhood. The neurological disease advanced in an orderly fashion through its successive stages, finally affecting the whole nervous system and leading to death before the age of 40 years. Dermatological and ocular damage of the XP-A patients tended to be limited. The two XP-C patients were neurologically and cognitively intact despite mild brain atrophy as seen by neuroimaging. The XP-G patients had sensorineural hearing loss, laryngeal dystonia and peripheral neuropathy. The XP-C patients had severe skin and ocular malignancies that first presented at pre-school age. They also showed immunosuppression in cell-mediated immunity. Neurological disease appears to be associated with the complementation group and the failure of fibroblasts to recover RNA synthesis following UV irradiation, but not necessarily to the severity of the dermatological symptoms, the hypersensitivity of fibroblasts to UVB killing or the susceptibility of keratinocytes to UVB-induced apoptosis.
Assuntos
Encefalopatias/etiologia , Xeroderma Pigmentoso/psicologia , Adulto , Criança , Pré-Escolar , Reparo do DNA , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Oftalmopatias/etiologia , Feminino , Finlândia , Teste de Complementação Genética , Transtornos da Audição/etiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Mutação , Testes Neuropsicológicos , Proteínas Nucleares/genética , Estudos Prospectivos , Dermatopatias/etiologia , Tomografia Computadorizada por Raios X , Fatores de Transcrição/genética , Xeroderma Pigmentoso/complicações , Proteína de Xeroderma Pigmentoso Grupo A/genéticaRESUMO
Replicative DNA polymerases are blocked at DNA lesions. Synthesis past DNA damage requires the replacement of the replicative polymerase by one of a group of specialised translesion synthesis (TLS) polymerases, most of which belong to the Y-family. Each of these has different substrate specificities for different types of damage. In eukaryotes mono-ubiquitination of PCNA plays a crucial role in the switch from replicative to TLS polymerases at stalled forks. All the Y-family polymerases have ubiquitin binding sites that increase their binding affinity for ubiquitinated PCNA at the sites of stalled forks.